1-carboxy-1-vinyloxyimino aminothiazole cephalosporin derivatives

ABSTRACT

The present invention relates to a compound having the formula: ##STR1## wherein R is a hydrogen atom, a carboxyl-protecting group or a negative charge and Q is a hydrogen atom, a halogen atom, a hydroxyl group, an acetoxy group, a carbamoyl group, an azide group, a substituted or unsubstituted quarternary ammonio group or a substituted or unsubstituted heterocyclic thio group having at least one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or a non-toxic salt or physiologically hydrolyzable non-toxic ester thereof; a process for producing it; and an antibacterial agent comprising it as an active ingredient. 
     Further, the present invention also relates to a compound having the formula: ##STR2## wherein R 3  is a hydrogen atom or an amino-protecting group, and each of R 4  and R 5  which may be the same or different is a hydrogen atom or a carboxyl-protecting group, or a salt thereof; and a process for producing it.

TECHNICAL FIELD

The present invention relates to novel cephalosporin derivatives, aprocess for their production, antibacterial agents containing them asactive ingredients and intermediates for their production.

BACKGROUND TECHNOLOGY

Heretofore, a number of compounds have been synthesized which have a2-substituted oxyiminoacetamide group as a side chain at the 7-positionof the cephem nucleus. For example, there may be mentioned a2-(2-aminothiazol-4-yl)-2-substitued oxyiminoacetamide group, a2-(2-aminoxazol-4-yl)-2-substituted oxyiminoacetamide group, a2-(5-amino-1,2,4-thiadiazol-3-yl)-2-substituted oxyiminoacetamide group,a 2-(furyl-2-yl)-2-substituted oxyiminoacetamide group or a2-substituted phenyl-2-substituted oxyiminoacetamide group. Aspublications which disclose such compounds, for example, JapaneseUnexamined Patent Publications No. 52083/1975, No. 102293/1977, No.116492/1977, No. 137988/1978, No. 154786/1979, No. 157596/1979, No.154980/1980, No. 86187/1981, No. 59895/1982, No. 99592/1982, No.158769/1982, No. 192394/1982, No. 8087/1983 and No. 174387/1983, and TheChemical Society of Japan, Vol. 5, p.785-805 (1981), may be mentioned.It is disclosed that such compounds exhibit antibacterial activitiesagainst Gram-positive bacteria and Gram-negative bacteria includingPseudomonas aeruginosa thus suggesting that they have excellentantibacterial activities and a broad antibacterial spectrum.

In addition to the above publications, as the prior arts concerning thepresent invention, Japanese Unexamined Patent Publications No.9296/1979, No. 162592/1983, No. 108792/1984, No. 130294/1984, No.34972/1985, No. 67483/1985 and No. 97982/1985, may be mentioned. In theclaims of such publications, as substituents of the2-(2-aminothiazol-4-yl)-2-substituted oxyiminoacetamide group at the7-position of the cephem nucleus, a number of substituents are mentionedincluding an alkyl group and an alkenyl group. Further, the descriptionof the alkenyl group is general referring, for example, to an alkenylgroup which may be substituted, or a substituted unsubstituted C₂ -C₈alkenyl group. However, the alkenyl group suggested by the specificdisclosure and examples in the specifications is an unsubstitutedalkenyl group such as a vinyl group or an allyl group. Further, as thealkenyl group substituted by a carboxyl group, there is only a1-carboxylate allyl group, and there is no disclosure or suggestionconcerning the 1-carboxy-1-vinyl group in the above prior artreferences. Further, with respect to the prior art relating tointermediates, a number of 2-substituted oxyiminoacetic acid derivativeshave been synthesized as the acyl side chain acid at the 7-position ofthe cephem nucleus. As such an acyl side chain acid, for example, a2-(2-aminothiazol-4-yl)-2-substituted oxyiminoacetic acid, a2-(thiazol-4-yl)-2-substituted oxyiminoacetic acid, a2-(2-aminooxazol-4-yl)-2-substituted oxyiminoacetic acid, a2-(5-amino-1,2,4-thiadiazol-3-yl)-2-substituted oxyiminoacetic acid a2-(furyl-2-yl)-2-substituted oxyiminoacetic acid or a 2-(substitutedphenyl)-2-substituted oxyiminoacetic acid, may be mentioned. As thepublications describing such 2-substituted oxyiminoacetic acidcompounds, for example, Journal of the Japanese Chemical Society,p.785-804 (1981), the J. of Antibiotics, Vol. 34, p.1447-1455 (1981),ditto Vol. 35, p.712-720 (1982), ditto Vol. 36, p.1205-1210 (1983),ditto Vol. 37, p.532-571 (1984) and ditto Vol. 39, p.111-127 andp.404-414 ( 1986) may be mentioned. As the substituents of suchsubstituted oxyimino groups, for example, lower alkyl, lower alkenyl,lower alkynyl, aralkyl and aryl groups which may have one or moresubstituents such as a hydroxyl group, a carboxyl group, a carbamoylgroup, a cyano group, an amino group, a halogen atom, an alkyl group andan aryl group, are generally known.

Further, a 2-(1-vinyloxyimino)acetic acid derivative having a vinylgroup as a substituent of the substituted oxyimino group is described inJapanese Unexamined Patent Publication No. 22392/1979 (corresponding toGer. Offen., 2,831,332; Chem. Abstr., 90-168630n), and synthesized asshown by the following reaction scheme. ##STR3## In the formulas, X is achlorine atom, a bromine atom or an iodine atom and alk is an alkylgroup having from 1 to 4 carbon atoms.

This publication discloses only the 2-(1-vinyloxyimino)acetic acidderivative, and no synthesis or suggestion for a2-(1-carboxy-1-vinyloxyimino)acetic acid derivative of the presentinvention is given.

β-lactam antibiotics exhibit selective toxicity only against bacteriaand give no substantial affects against animal cells, and they have beenwidely used for the treatment of infectious diseases caused by bacteria,as antibiotics having no substantial side effects. Thus, they are highlyuseful drugs. However, in recent years, the isolating frequency ofresistant Gram-positive bacteria and resistant glucose non-fermentativeGram-negative rods, as causative organisms tends to increase. Therefore,it is desired to increase the activities of antibiotics against suchbacteria.

It is an object of the present invention to provide novel cephalosporinderivatives having excellent antibacterial activities. Variouscephalosporin derivatives have been synthesized which have a2-substituted oxyiminoacetamide group at the 7-position of the cephemnucleus. With respect to a compound having a 1-carboxy-1-vinyloxyiminogroup as such substituted oxyimino group, however, there is nodisclosure in patent specifications, not to mention its synthesis.

Namely, the compound of the present invention having a2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamide group atthe 7-position of the cephem nucleus is a novel compound not disclosedin literatures. The present inventors have found that the compound ofthe present invention have strong antibacterial activities againstsensitive or resistant Gram-negative bacteria and Gram-positive bacteriaand excellent stability against β-lactamase. The present invention hasbeen accomplished on the basis of the discovery.

Further, the present inventors have conducted extensive researches todevelop 2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetic acidderivatives and a process for their production. As the results, it hasbeen found that when the 2-(2-aminothiazol-4-yl)glyoxylic acidderivative of the formula VI is reacted withO-(1-carboxy-1-vinyl)hydroxylamine derivative of the formula V, and ifnecessary, the protecting group is removed, it is possible to obtain thecompound of the present invention having the formula III in good yield.The present invention has been accomplished on the basis of thediscovery.

DISCLOSURE OF THE INVENTION

The present invention provides a compound having the formula: ##STR4##wherein R is a hydrogen atom, a carboxyl-protecting group or a negativecharge and Q is a hydrogen atom, a halogen atom, a hydroxyl group, anacetoxy group, a carbamoyloxy group, an azide group, a substituted orunsubstituted quarternary ammonio group or a substituted orunsubstituted heterocyclic thio group having at least one hetero atomselected from the group consisting of a nitrogen atom, an oxygen atom,or a sulfur atom, or a non-toxic salt or physiologically hydrolyzablenon-toxic ester thereof, a process for producing it and an antibacterialagent comprising it as an active ingredient.

Further, the present invention provides a compound having the formulaIII which is an intermediate for producing the compound of the formulaI. ##STR5## wherein R³ is a hydrogen atom or an amino-protecting group,and each of R⁴ and R⁵ which may be the same or different is a hydrogenatom or a carboxyl-protecting group, or a salt thereof and a process forproducing it.

Now, the symbols and terms used in the present specification will beexplained.

The lower alkyl group is a straight chain, branched chain or cycliclower alkyl group.

The straight chain or branched chain lower alkyl group is an alkyl grouphaving from 1 to 6 carbon atoms. Specifically, a methyl group, an ethylgroup, a n-propyl group, an isopropyl group, a n-butyl group, anisobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl groupor a n-hexyl group may be mentioned. A methyl group, an ethyl group, an-propyl group or an isopropyl group is particularly preferred.

The cyclic lower alkyl group is a cyclic alkyl group having from 3 to 6carbon atoms. Specifically, a cyclopropyl group, a cyclobutyl group, acyclopentyl group or a cyclohexyl group may be mentioned. A cyclopropylgroup, a cyclobutyl group or a cyclopentyl group is particularlypreferred.

The lower alkenyl group is an alkenyl group having from 2 to 6 carbonatoms. Specifically, a vinyl group, an allyl group, an isopropenylgroup, a 1,1-dimethylallyl group, a 2-butenyl group or a 3-butenyl groupmay be mentioned.

The lower alkynyl group is an alkynyl group having from 2 to 3 carbonatoms. Specifically, an ethynyl group or a 2-propynyl group may bementioned.

The lower alkoxy group is an alkoxy group having from 1 to 4 carbonatoms. Specifically, a methoxy group, an ethoxy group, a propoxy group,an isopropoxy group, a butoxy group or an isobutoxy group may bementioned. A methoxy group or an ethoxy group is particularly preferred.

As the alkanoyloxy group, for example, an acetoxy group, a propionyloxygroup or a butyryloxy group may be mentioned. An acetoxy group isparticularly preferred.

The lower alkoxycarbonyl group is an alkoxycarbonyl group having from 2to 5 carbon atoms. Specifically, it may be a methoxycarbonyl group, anethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonylgroup, a butoxycarbonyl group or an isobutoxycarbonyl group. Amethoxycarbonyl group or an ethoxycarbonyl group is particularlypreferred.

The substituted or unsubstituted amino group represents an amino groupand an amino group substituted by an alkyl group having from 1 to 4carbon atoms, for example, an alkylamino group such as a methylaminogroup, an ethylamino group, a dimethylamino group or anN-ethylmethylamino group, a formylamino group or an alkanoylamino groupsuch as an acetylamino group, a propionylamino group or a butyrylaminogroup. An amino group, a methylamino group, a dimethylamino group, aformylamino group or an acetylamino group is particularly preferred.

The substituted imino group represents a hydroxyimino group, an iminogroup substituted by an alkoxy group having from 1 to 4 carbon atoms,for example, an alkoxyimino group such as a methoxyimino group, anethoxyimino group or a propoxyimino group, or a carboxymethoxyiminogroup. A hydroxyimino group, a methoxyimino group or acarboxymethoxyimino group is particularly preferred.

The fluoroalkyl group represents a fluorine-substituted alkyl grouphaving from 1 to 4 carbon atoms such as a fluoromethyl group, atrifluoromethyl group or a 2-fluoroethyl group. A trifluoromethyl groupor a 2-fluoroethyl group is particularly preferred.

The aryl group represents an aryl group having from 6 to 12 carbon atomssuch as a phenyl group or a naphthyl group. A phenyl group isparticularly preferred. As the heterocyclic group having at least onehetero atom selected from the group consisting of a nitrogen atom, anoxygen atom and a sulfur atom, there may be mentioned, for example, athienyl group, a furyl group, an imidazolyl group, a pyrazolyl group, athiazolyl group, an isothiazolyl group, an oxazolyl group, anisooxazolyl group, a triazolyl group, a thiadiazolyl group, anoxadiazolyl group, a tetrazolyl group, a pyridyl group, a pyrazinylgroup, a pyridazinyl group or a triazinyl group. An oxazolyl group, athiazolyl group, an oxadiazolyl group, a thiadiazolyl group or atetrazolyl group is particularly preferred.

The halogen atom is a fluorine atom, a chlorine atom, a bromine atom oran iodine atom.

The substituted or unsubstituted quaternary ammonio group is aquaternary ammonio group which has been known as the substituent at the3-position of the cephem nucleus. Preferred is a substituted orunsubstituted quaternary ammonio group having the formula: ##STR6##wherein each of R^(a), R^(b) and R^(c) which may be the same ordifferent is a lower alkyl group, a lower alkenyl group or a loweralkynyl group, or two or three of R, R and R bond each other, andtogether with the adjacent nitrogen atom, form a saturated orunsaturated monocyclic, polycyclic or cross-linked polycyclic groupwhich may contain at least one hetero atom selected from the groupconsisting of an oxygen atom, a nitrogen atom or a sulfur atom, whereineach of said lower alkyl, lower alkenyl, lower alkynyl, monocyclic,polycyclic and cross-linked polycyclic group may be substituted by oneor more substituents which may be the same or different, selected fromthe group consisting of a hydroxyl group, a lower alkoxy group, aformyloxy group, an alkanoyloxy group, a carbamoyloxy group, a hydroxylower alkyl group, a sulfo lower alkyl group, a carboxy lower alkylgroup, a carbamoyl lower alkyl group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a cyano group, a sulfo group, asulfamoyl group, a substituted or unsubstituted amino group, a halogenatom, an aryl group and a nitrogen atom, an oxygen atom and a sulfuratom, provided that each of said aryl and aromatic heterocylic groupsmay have one or more substituents which may be the same or different,selected from the group consisting of a lower alkyl group, a loweralkenyl group, a lower alkynyl group, a fluoroalkyl group, a loweralkoxy group, an alkanoyloxy group, a carbamoyloxy group, a carboxylgroup, a lower alkoxycarbonyl group, a carbamoyl group, a cyano group, asulfo group, a sulfamoyl group, a substituted or unsubstituted aminogroup, a substituted oxyimino group and a halogen atom.

The saturated or unsaturated monocyclic, polycyclic or cross-linkedpolycyclic group which may contain at least one hetero atom selectedfrom the group consisting of an oxygen atom, a nitrogen atom and asulfur atom, which may be formed by two or two of said R, R and Rtogether with the adjacent nitrogen atom, includes, for example, anazetidinio group, a pyrrolidinio group, a piperidinio group, a3-oxopiperidinio group, a 4-oxopiperidinio group, a1,2,3,6-tetrahydropiperidinio group, a hexamethyleneiminio group, amorpholinio group, a thiomorpholinio group, a 3-oxomorpholinio group, apiperadinio group, a homopiperadinio group, a 3-oxopiperadinio group, anisoindolinio group, a 1,2,3,4-tetrahydroisoquinolinio group, a2,3,4,5-tetrahydro-1H-2-benzazepinio group, a1,2,4,5-tetrahydro-3H-3-benzazepinio group, an imidazolinio group, apyrimidinio group, an oxazolinio group, a pyridazinio group, athiazolinio group, a pyridinio group, a quinolinio group, anisoquinolinio group, a 1H-imidazo[4,5-b]pyridinio group, athiazolo[4,5-b]pyridinio group, an oxazo[4,5-b]pyridinio group, a1H-2-methylimidazo[4,5-b]pyridinio group, a3-methyl-3H-imidazo[4,5-b]pyridinio group, a1-methyl-1H-imidazolo[4,5-c]pyridinio group, a1-methyl-1H-imidazolo[4,5-c]pyridinio group, a 5-aminoisoquinoliniogroup, a 5-hydroxyisoquinolinio group, a 6-acetoxyisoquinolinio group, a5,6-diacetoxyisoindolinio group, a 5,6-dihydroxyisoindolinio group, a4-carboxypyridinio group, a 4-sulfopyridinio group, a4-carbamoylpyridinio group, a 4-(oxazol-2-yl)pyridinio group, a4-(4,5-dihydrooxazol-2-yl)pyridinio group, a 2,3-cyclopentenopyridiniogroup, a 3,4-cyclopentenopyridinio group, a 3,4-cyclohexenopyridiniogroup, a 3-aminopyridinio group, a 4-(2-carboxyethyl)pyridinio group, a4-sulfomethylpyridinio group, a 4-(2-sulfoethyl)pyridinio group, a3-formamidopyridinio group, a 3-acetamidopyridinio group, a2-hydroxymethylpyridinio group, a dihydrofuranopyridinio group, a3-hydroxymethylpyridinio group, a 4-hydroxymethylpyridinio group, a4-(2-hydroxyethyl)pyridinio group, a 3-carboxypyridinio group, a4-carboxypyridinio group, a 3-carboxymethylpyridinio group, a3-(2-carboxyethyl)pyridinio group, a 3-carbamoylpyridinio group, a3-carbamoylmethylpyridinio group, a 3-(2-carbamoylethyl)pyridinio group,a 4-(2-carbamoylethyl)pyridinio group, a 3-fluoropyridinio group, a4-fluoropyridinio group, a 3-chloropyridinio group, a 4-chloropyridiniogroup, a 3-bromopyridinio group, a 4-bromopyridinio group, a3-trifluoromethylpyridinio group, a 4-trifluoromethylpyridinio group, a4-(2-fluoroethyl)pyridinio group, a sulfamoylpyridinio group, a1-azoniabicyclo[2.2.1]pentan-1-yl group, a1-azoniabicyclo[3.3.1]nonan-1-yl group, a quinuclidinio group and a2-dehydroquinuclidinio group.

The substituted or unsubstituted heterocyclic thio group having at leastone hetero atom selected from the group consisting of a nitrogen atom,an oxygen atom or a sulfur atom, includes, for example, a substituted orunsubstituted thienylthio, furylthio, imidazolylthio, pyrazolylthio,thiazolylthio, isothiazolylthio, oxazolylthio, isooxazolylthio,triazolylthio, thiadiazolylthio, oxadiazolylthio, tetrazolylthio,pyridylthio, pyradinylthio, pyridadinylthio and triazinylthio group. Thesubstituent of said heterocyclic thio group is one or more substituentswhich may be the same or different, selected from the group consistingof a lower alkyl group which may be susbstituted by, for example, ahydroxyl group, an alkanoyl group, a carbamoyloxy group, a carboxylgroup, a carbamoyl group, a cyano group, a sulfo group, a sulfamoylgroup, a substituted or unsubstituted amino group, a substituted iminogroup or a halogen atom, and for example, a lower alkoxy group, aformyloxy group, an alkanoyloxy group, a carbamoyloxy group, afluoroalkyl group, an alkylidene group of the formula --(CH₂)₃ 5 --, acarboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a cyanogroup, a sulfo group, a sulfamoyl group, a substituted or unsubstitutedamino group, a substituted imino group, a halogen atom, an aryl groupand a heterocyclic group having at least one hetero atom selected fromthe group consisting of a nitrogen atom, an oxygen atom and a sulfuratom. However, each of said aryl and heterocyclic groups may have one ormore substituents which may be the same or different, selected from thegroup consisting of a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a fluoroalkyl group, a hydroxyl group, a lower alkoxygroup, an alkanoyloxy group, a carbamoyloxy group, a carboxyl group, alower alkoxycarbonyl group, a carbamoyl group, a cyano group, a sulfogroup, a sulfamoyl group, a substituted or unsubstituted amino group, asubstituted oxyimino group, a halogen atom.

Further, said heterocyclic thio group may be condensed with a benzenenucleus. For example, a 2-benzoxazolylthio group, a 2-benzothiazolylthiogroup or a 2-benzoimidazolylthio group may be mentioned.

Said benzene nucleus may have a substituent. For example, the saidbenzene nucleus may have one or more substituents which may be the sameor different, selected from the group consisting of a lower alkyl group,a hydroxyl group, a fluoroalkyl group, a lower alkoxy group, a formyloxygroup, an alkanoyloxy group, a carbamoyloxy group, a fluoroalkyl group,an alkylidene group of the formula --(CH₂)₃ 5 --, a carboxyl group, alower alkoxycarbonyl group, a carbamoyl group, a cyano group, a sulfogroup, a sulfamoyl group, a substituted or unsubstituted amino group, asubstituted imino group, a halogen atom, an aryl group and aheterocyclic group having at least one hetero atom selected from thegroup consisting of a nitrogen atom., an oxygen atom and a sulfur atom.However, each of said aryl and heterocyclic groups may have one or moresubstituents which may be the same or different, selected from the groupconsisting of a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a fluoroalkyl group, a hydoxyl group, a lower alkoxygroup, an alkanoyloxy group, a carbamoyloxy group, a carboxyl group, alower alkoxycarbonyl group, a carbamoyl group, a cyano group, a sulfogroup, a sulfamoyl group, a substituted or unsubstitued amino group, asubstituted oxyimino group, a halogen atom.

As the substituted or unsubstituted heterocyclic thio group having atleast one hetero atom selected from the group consisting of a nitrogenatom, an oxygen atom and a sulfur atom, there may be mentioned, forexample, a (1,3,4-oxazol-2-yl)thiomethyl group, a(5-methyl-1,3,4-oxadiazozol-2-yl)thiomethyl group, a(5-carboxymethyl-1,3,4-oxadiazol-2-yl)thiomethyl group, a[5-(3,4-hydroxyphenyl)-1,3,4-oxadiazole]thiomethyl group, a[5-(3,4-diacetoxyphenyl)-1,3,4-oxadiazole]thiomethyl group, a(5-carboxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl group, a[5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]thiomethyl group, a[5-(3,4-diacetoxyphenyl)-1,3,4-thiadizol-2-yl]thiomethyl group, a(thiazol-2-yl)thiomethyl group, a (4-methylthiazol-2-yl)thiomethylgroup, a (5-carboxymethylthiazol-2-yl)thiomethyl group, a(4-methyl-5-carboxymethylthiazol-2-yl)thiomethyl group, a(4-phenyl-5-carboxymethylthiazol-2-yl)thiomethyl group, a4-(3,4-dihydroxyphenyl)-5-carboxymethylthiazol-2-yl]thiomethyl group, a[4-(3,4-diacetoxyphenyl)-5-carboxymethylthiazol-2-yl]thiomethyl group, a(4-carboxythiazol-2-yl)thiomethyl group, a4-carboxy-5-(3'-4-dihydorxyphenyl)thiazol-2-yl]thiomethyl group, a[4-carboxy-5-(3,4-diacetoxyphenyl)thiazol-yl]thiomethyl group, a(oxazol-2-yl)thiomethyl group, a5-(3,4-dihydroxyphenyl)oxazol-2-yl]thiomethyl group, a5-(3,4-diacetoxyphenyl)oxazol-2-yl]thiomethyl group, a(benzoimidazol-2-yl)thiomethyl group, a(1-methylbenzoimidazol-2-yl)thiomethyl group, a(5,6-dihydroxybenzoimidazol-2-yl)thiomethyl group, a(5,6-diacetoxybenzoimidazol-2-yl)thiomethyl group, a(5,6-dihydroxy-1-methylbenzoimidazol-2-yl)thiomethyl group, a(5,6-diacetoxy-1-methylbenzoimidazol-2-yl)thiomethyl group, a(benzooxazol-2-yl)thiomethyl group, a(5,6-dihydroxybenzooxazol-2-yl)thiomethyl group, a(5,6-diacetoxybenzooxazol-2-yl)thiomethyl group, a(benzothioazol-2-yl)thiomethyl group, a(5,6-dihydroxybenzothiazol-2-yl)thiomethyl group, a(5,6-diacetoxybenzothiazol-2-yl)thiomethyl group, or the like.

Further, the moiety in the oxyimino group in the formula I, includes asyn-isomer (Z-configuration) and an anti-isomer (E-configuration).Generally, the syn-isomer exhibits superior antibacterial activities. Inthis specification, the substituted oxyimino group represents thesyn-isomer in all cases. The nomenclature for E and Z configurations isgiven in Journal of the American Chemical Society, Vol. 90, p.509(1968).

The compounds of the formula I may be converted to non-toxic salts orphysiologically hydrolyzable non-toxic esters thereof by usual methods.The non-toxic salts of the compounds of the formula I meanpharmaceutically acceptable usual salts, i.e. salts at the carboxylgroup at the 4-position of the cephem nucleus, at the 1-carboxy-1-vinylgroup at the 7-position of the cephem nucleus, at the 2-aminothiazolegroup at the 7-position of the cephem nucleus, and at a carboxyl groupor a sulfo group or at the basic residue such as an amino group, whichis substituted at Q.

The preferred salts for the formula I include, for example, a salt witha metal such as sodium, potassium, calcium, magnesium or aluminum, asalt with an organic amine such as N,N'-dibenzylethylenediamine orprocaine, a salt of an inorganic acid such as hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid or perchloric acid, a saltwith an organic acid such as acetic acid, lactic acid, propionic acid,maleic acid, fumaric acid, maleic acid, tartaric acid or citric acid, asalt with a sulfonic acid such as methanesulfonic acid, isethionic acidor p-toluenesulfonic acid and a salt with an amino acid such as glutamicacid, aspartic acid, lysine or arginine.

The non-toxic esters of the formula I mean pharmaceutically acceptableusual esters at the carboxyl groups at the 4-position of the cephemnucleus. For example, there may be mentioned an alkanoyloxymethyl groupsuch as an acetoxymethyl group or a pivaloyloxymethyl group, analkoxycarbonyloxyalkyl group such as a 1-(ethoxycarbonyloxy)ethyl groupor a 1-(isopropoxycarbonyloxy)ethyl group, a phthalidyl group or a(5-substituted-2-oxo-1,3-dioxol-4-yl)methyl group such as a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group.

It is the feature of the compound of the present invention to have a1-carboxy-1-vinyloxyimino structure as a moiety for the side chain atthe 7-position of the cephem nucleus. There is no particular restrictionas to the side chain at the 3-position of the cephem nucleus.

As the side chain at the 3-position of the cephem nucleus, side chainsusually used in the field of the cephalosporin chemicals may beexemplified. Typical examples include, for example, a methyl group, achloromethyl group, a bromomethyl group, an iodomethyl group, ahydroxymethyl group, an acetoxymethyl group, a carbamoyloxy group, anazidomethyl group, a methoxymethyl group, an ethoxymethyl group, amethylthiomethyl group, an ethylthiomethyl group, a(tetrazol-5-yl)thiomethyl group, a (1-methyltetrazol-5-yl)thiomethylgroup, a (1-hydroxymethyltetrazol-5-yl)thiomethyl group, a[1-(2-hydroxyethyl)tetrazol-5-yl]thiomethyl group, a(1-carboxymethyltetrazol-5-yl)thiomethyl group, a(1-sulfomethyltetrazol-5-yl)thiomethyl group, a[1-(2-sulfoaminoethyl)tetrazol-5-yl]thiomethyl group, a(1-dimethylaminomethyltetrazol-5-yl)thiomethyl group, a[1-(2-dimethylaminoethyl)tetrazol-5-yl]thiomethyl group, a(1-carboxymethyltetrazol-5-yl)thiomethyl group, a(1,2,3-triazol-4-yl)thiomethyl group, a(3-methyl-1,2,3-triazol-4-yl)thiomethyl group, a(5-methyl-1,2,3-triazol-4-yl)thiomethyl group, a(1,2,4-triazol-5-yl)thiomethyl group, a pyridiniomethyl group, a2,3-cyclopentenopyridiniomethyl group, a 3,4-cyclopentenopyridiniomethylgroup, a 2,3-cyclohexenopyridiniomethyl group, a3,4-cyclohexenopyridiniomethyl group, a2,3-dihydrofuro[2,3-b]pyridiniomethyl group, a2,3-dihydrothieno[2,3-b]pyridiniomethyl group, a 3-aminopyridiniomethylgroup, a 3-formamidopyridiniomethyl group, a 3-acetamidopyridiniomethylgroup, a 2-hydroxymethylpyridiniomethyl group, a3-hydroxymethylpyridiniomethyl group, a 4-hydroxymethylpyridiniomethylgroup, a 3-(2-hydroxyethyl)pyridiniomethyl group, a4-(2-hydroxyethyl)pyridiniomethyl group, a 3-carboxypyridiniomethylgroup, a 4-carboxypyridiniomethyl group, a3-carboxymethylpyridiniomethyl group, a3-(2-carboxyethyl)pyridiniomethyl group, a4-(2-carboxyethyl)pyridiniomethyl group, a 3-carbamoylpyridin-iomethylgroup, a 4-carbamoylpyridiniomethyl group, a3-carbamoylmethylpyridiniomethyl group, a4-carbamoylmethylpyridiniomethyl group, a3-(2-carbamoylethyl)pyridiniomethyl group, a4-(2-carbamoylethyl)pyridiniomethyl group, a4-sulfomethylpyridiniomethyl group, a 4-(2-sulfoethyl)pyridiniomethylgroup, a 3-fluoropyridiniomethyl group, a 4-fluoropyridiniomethyl group,a 3-chloropyridiniomethyl group, a 4-chloropyridiniomethyl group, a3-bromopyridiniomethyl group, a 4-bromopyridiniomethyl group, a3-trifluoromethylpyridiniomethyl group, a4-trifluoromethylpyridiniomethyl group, a[1-(2-dimethylaminoethyl)tetrazol-5-yl]thiomethyl group, a1,2,3-triazol-5-yl group, a(4-methyl-5-carboxymethylthiazol-2-yl)thiomethyl group, a(3-hydroxy-4-carboxyisothiazol-5-yl)thiomethyl group, a(1-methyl-3-carboxy-1,2,4-triazol-5-yl)thiomethyl group, a(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thiomethyl group,a (1,2,5,6-tetrahydro-5,6-dioxoas-triazin-3-yl)thiomethyl group, a(2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl)thiomethyl group, a(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thiomethyl group,a (2,5-hydroxy-2-methyl- 5-oxo-6-methoxy-as-triazin-3-.yl)thiomethylgroup, a (5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl group, a(1,3,4-thiadiazo1-2-yl)thiomethyl group, a4-ethoxycarbonyl-1-methyl-1-piperadiniomethyl group, a1-methyl-1-hexamethyleneiminiomethyl group, a1,4-dimethyl-1-piperadiniomethyl group, a1-methyl-1,2,3,6-tetrahydropyridiniomethyl group, a4-acetyl-1-methylpiperadiniomethyl group, a3-(1,2,4-oxodiazol-3-yl)pyridiniomethyl group, a3-(imidazol-2-yl)pyridiniomethyl group, a 1-methylpyrrolidiniomethylgroup, a 2-methylisoindoliniomethyl group, a2-methyl-5,6-dihydroxyisoindoliniomethyl group, a2-methyl-5,6-diacetoxyisoindoliniomethyl group, a2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoliniomethyl group, anisoquinolinio group, a quinoliniomethyl group, a 6,7-dihydroxyquinoliniogroup and a 6,7-diacetoxyquinolinio group.

The preferred examples of the compound of the formula I provided by thepresent invention, are as follows:

1)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

2)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn-isomer)

3)7β-[2-aminothiazol-4-yl)-2-(1-carboxy.-1-7β-[2-vinyloxyimino)acetamido]-3-(4-methyl-5-carboxymethylthiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

4)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(5-methyl-1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

5) 7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-10vinyloxyimino)acetamido]-3-[1-(2-dimethylaminoethyl)tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

6)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)thiazol-2-yl]-3-cephem-4-carboxylicacid (syn-isomer)

7)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(3,4-diacetoxyphenyl)-5-carboxymethylthiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

8)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[1-(2-hydroxyethyl)tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

9)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carboxy-3-hydroxyisothiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)

10)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

11)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

12)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(2,3-cychlopenteno-1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

13)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

14)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

15)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

16)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

17)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-sulfonatomethyl-1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

18)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(2-sulfonatoethyl)-1-pyridinio]methyl-3-cephem-4-carboxylicacid (syn-isomer)

19)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-amino-1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

20)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-formylamino-1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

21)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

22)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

23)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-oxazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

24)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)oxazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

25)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-carboxy-5-(3,4-dihydroxyphenyl)thiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

26)3-[4-(3,4-diacetoxyphenyl)-5-carboxymethylthiazol-2-yl]thiomethyl-7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-cephem-4-carboxylicacid (syn-isomer)

27)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]cephalosporanicacid (syn-isomer)

28)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-methyl-1,3,4-oxadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

29)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn-isomer)

30)7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(1-carboxymethyltetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)

The moiety in the oxyimino group in the formula III, includes asyn-isomer (Z-configuration) and an anti-isomer (E-configuration). Inthis specification, the substituted oxyimino group is preferably thesyn-isomer. However, said syn-isomer may include a small amount of theanti-isomer. The preferred examples of the compound of the formula IIIprovided by the present invention, are as follows:

1) 2-(aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetic acid

2) 2-(aminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-vinyloxyimino)aceticacid

3)2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-vinyloxyimino)aceticacid

4)2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-formamidothiazol-4-yl)aceticacid

5)2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid

6)2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-chloroacetamidothiazol-4-yl)aceticacid

7)2-(aminothiazol-4-yl)-2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)aceticacid

8)2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)aceticacid

9)2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-formamidothiazol-4-yl)aceticacid

10)2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid

11)2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-chloroacetamidothiazol-4-yl)aceticacid

12) Methyl2-(aminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-vinyloxyimino)acetate

13) Methyl2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-vinyloxyimino)acetate

14) Methyl2-1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(formamidothiazol-4-yl)acetate

15) Methyl2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetate

16) Methyl2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-chloroacetamidothiazol-4-yl)acetate

17) Methyl2-(aminothiazol-4-yl)-2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)acetate

18) Methyl2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)acetate

19) Methyl2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-formamidothiazol-4-yl)acetate

20) Methyl2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetate

21) Methyl2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-chloroacetamidothiazol-4-yl)acetate

Now, the process for the preparation of the compounds of the presentinvention will be described.

The compound of the formula I of the present invention can be preparedby acylating a compound of the formula: ##STR7## wherein R² is ahydrogen atom, a carboxyl-protecting group or a negative charge, Q² is ahydrogen atom, a halogen atom, a hydroxy group, an acetoxy group, acarbamoyloxy group, an azide group, a substituted or unsubstitutedquarternary ammonio group or a substituted or unsubstituted heterocyclicthio group having at least one hetero atom selected from the groupconsisting of a nitrogen atom, an oxygen atom or a sulfur atom, and Y isS or SO, provided that Q² and substituents thereof may be protected, ora salt thereof, with a carboxylic acid of the formula: ##STR8## wherein,R³ is a hydrogen atom or an amino-protecting group and R⁴ is a hydrogenatom or a carboxyl-protecting group, or a reactive derivative thereof,to form a compound having the formula: ##STR9## wherein R², R³, R⁴, Q²and Y are as defined above, or a salt thereof, and, if necessary,reacting a nucleophilic agent to the compound of the formula II-1wherein Q² is a leaving group, or a salt thereof to form a compoundhaving the formula: ##STR10## wherein R², R³, R⁴ and Y are as definedabove and Q³ is a halogen atom, a hydroxyl group, a carbamoyloxy group,an azide group, a substituted or unsubstituted quarternary ammonio groupor a substituted or unsubstituted heterocyclic thio group having atleast one hetero atom selected from the group consisting of a nitrogenatom, an oxygen atom or a sulfur atom, or a salt thereof, and then, ifnecessary, reducing the compound of the formula II-1 or II-2, or a saltthereof and/or removing the protecting group from the compound of theformula II-1 or II-2, or a salt thereof.

When Q² is a leaving group in the compound of the formula II-1, as sucha leaving group, there may be specifically mentioned a halogen atom suchas chlorine, bromine or iodine, an acetoxy group or a carbamoyloxygroup. A chlorine atom, a bromine atom, an iodine atom or an acetoxygroup is particularly preferred.

Further, the nucleophilic agent reacting with the compound of theformula II-1 includes all nucleophilic agents usually used in the fieldof the cephalosporin chemicals.

As the nitrogen nucleophilic agent, there may be mentioned, for example,a tertiary aliphatic amine derivative, an aromatic amine derivative, anaromatic aliphatic amine derivative or a cyclic amine derivative,-aswell as a pyrimidine, purine, pyridazine, pyrazine, pyrazole, imidazoleor triazole derivative which has at least one different hetero atom oran azide derivative.

As the sulfur nucleophilic agent, there may be mentioned adithiocarbamate derivative, an aromatic thioamide derivative, analiphatic thioamide derivative, a cyclic thioamide derivative, athiosulfate derivative, a thiol derivative, a thiophenol derivative or athio acid derivative. As such nucleophilic reagents, commerciallyreadily available ones can usually be used.

The mercapto derivative having the adjacent two hydroxyl or acetoxygroups, which provides the compound of the present invention, is a novelcompound not disclosed in any literature. The compound can be producedby the following methods.

A 2-mercapto-5-(3,4-disubstituted phenyl)-1,3,4-oxadiazole derivativecan be prepared by reacting a benzohydrazide derivative with carbondisulfide in an ethanol solvent in the presence of potassium hydroxide.

A 2-mercapto-5-(3,4-disubstituted phenyl)-1,3,4-thiadiazole derivativecan be prepared by the following method i or ii. (i) It can be preparedby reacting a 3,4-disubstituted thiobenzamide with hydrogen sulfide in apyridine solvent in the presence of triethylamine. (ii) It can beprepared by reacting a potassium 3-(3,4-disubstitutedbenzoyl)dithiocarbazate with concentrated sulfuric acid.

A 2-mercapto-4-(3,4-disubstituted phenyl)thiazole derivative can beprepared by reacting 2-chloro-3',4'-dihydroxyacetophenone which isprepared in accordance with the method disclosed in Chemical Abstracts,84-43639s (1976), with ammonium dithiocarbamate in a methanol solvent.

A 4-carboxy-5-(3,4-disubstituted phenyl)-2-mercaptothiazole derivativecan be prepared by converting piperonal as a starting material inaccordance with the method disclosed in Organic Syntheses, Coll. Voll.,II, p.11-12, 1-3 and 519-520, to a 3-(3,4-disubstituted phenyl)pyruvicacid, brominating the compound to obtain a 3-bromo-(3,4-disubstitutedphenyl)pyruvic acid, and further reacting ammonium dithiocarbamate thecompound.

A 5-carboxymethyl-2-mercaptothiazole derivative can be prepared byreacting veratrole with succinic anhydride in the presence of anhydrousaluminum chloride to obtain 3-(3,4-dimethoxybenzoyl)propionic acid,subjecting the compound to demethylation with hydrobromic acid to obtain3-(3,4-dihydroxybenzoyl)propionic acid, subjecting the compound toenol-lactonation in the presence of acetic anhydride and sodium acetate,reacting the resulting compound sequentially with N-bromosuccinimide andwith diphenyldiazomethane to obtain3-(3,4-diacetoxybenzoyl)-3-bromopropionate, and further reacting thecompound with ammonium dithiocarbamate.

A 2-mercapto-5-(3,4-disubstituted phenyl)oxazole derivative can beprepared by reacting 2-chloro-3',4'-dihydroxyacetophenone prepared inaccordance with the method disclosed in Chemical Abstract, 84-43639s(1976), with sodium azide to obtain an azide compound, conductingcatalytic reduction of the compound to convert it to2-amino-3',4'-dihydroxyacetophenone, and further reacting the compoundwith carbon disulfide in an ethanol solvent in the presence of sodiumethoxide in accordance with the method disclosed in Chemical Abstracts,67-43806t (1967).

A 2-mercaptobenzoimidazole derivative can be prepared by using veratroleas a starting material in accordance with the methods disclosed inSynthesis, p.1033 (1974) and in Organic Syntheses, Coll. Voll., IV, p.56(1963).

A 2-mercaptobenzooxazole derivative can be prepared by usingveratraldehyde as a starting material in accordance with the methodsdisclosed in Journal of the Chemical Society Perkin Transactions 1,p.1353 (1974), Canadian Journal of Chemistry, Vol. 44, p.1879 (1966) andJournal of Pharmaceutical Science, Vol. 76, p.1002 (1956). A2-mercaptobenzothiazole derivative can be prepared by conductingnitration and catalytic reduction by using veratrole as a startingmaterial, to obtain 3,4-dimethoxy-6-nitroaniline, converting thecompound to a diazonium salt, then, reacting the diazonium salt withpotassium O-ethyl dithiocarbonate to obtain O-ethylS-(3,4-dimethoxy-6-nitrophenyl) dithiocarbonate, and further conductinga reductive ring closure reaction with stannous chloride in an ethanolsolvent.

Now, the process for the preparation of the compound of the formula I ofthe present invention, will be described in detail.

The compound of the formula II-1 can be prepared by reacting thecompound of the formula IV with the carboxylic acid of the formula IIIor its reactive derivative (such as its acid halide, mixed anhydride oractivated ester). The reaction is conducted in a solvent inert to thereaction such as water, acetone, dioxane, acetonitrile, tetrahydrofuran,methylene chloride, chloroform, ethylene chloride, benzene, ethylacetate, N,N-dimethylformamide or dimethylsulfxide, or in a mixture ofsuch solvents by using from 1 to 1.5 mols of the carboxylic acid of theformula III or its reactive derivative relative to 1 mol of the compoundof the formula IV, and the reaction temperature is from -40° to 40° C.

When an acid halide is used as the reactive derivative of the formulaIII, the reaction is preferably conducted in the presence of anacid-absorbing agent such as triethylamine, N-methylmorpholine,N,N-diemthylaniline or pyridine.

The acid halide-forming reaction is carried out by using from 1 to 10mols, preferably from 1 to 1.5 mols of the halogenating agent such asthionyl chloride, phosphorus trichloride, phosphorus tribromide,phosphorus pentachloride, phosphorus oxychloride, oxalylchloride orphosgene, relative to 1 mol of the carboxylic acid of the formula III,at a reaction temperature of from -40 to 100°, preferably from -20° to20°, and the reaction is completed for from 10 to 120 minutes.

The mixed acid anhydride-forming reaction is conducted by using from 1to 1.2 mols of a chloroformate such as methyl chloroformate, ethylchloroformate or isobutyl chloroformate in the presence of from 1 to 1.2mols of an acid-absorbing agent such as triethylamine,N-methylmorpholine, N,N-dimethylaniline or pyridine, relative to 1 molof the carboxylic acid of the formula III. The reaction temperature isfrom -40° to 20°C., preferably from -20° to 5° C. The reaction time isfrom 10 to 60 minutes.

The active ester-forming reaction is conducted by using from 1 to 1.2mols of a N-hydroxy compound (such as N-hydroxysuccinimide or1-hydroxybenzotriazole) or a phenol compound (such as 4-nitrophenol,2,4-dinitrophenol or 2,4,5-trichlorophenol) and from 1 to 1.4 mols ofN,N'-dicychlohexylcarbodiimide, relative to 1 mol of the carboxylic acidof the formula III. The reaction temperature is from -10° to 50° C. Thereaction time is from 0.5 to 2 hours.

When the carboxylic acid of the formula III is used in the form of afree acid in the acylation reaction, the compound of the formula II-1may be prepared in the presence of a condensation agent, for example, acarbodiimide such as N,N'-dicychlohexylcarbodiimide, phosphorusoxychloride, or a phosphorus oxychloride adduct ofN,N-dimethylformamide.

Further, when Q² in the formula II-1 is a leaving group, the leavinggroup is optionally subjected to substitution reaction by a nucleophilicreagent. The substitution reaction can be conducted in water or anorganic solvent such as methylene chloride, chloroform, diethyl ether,ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile,N,N-dimethylformamide or dimethylsulfoxide, or in a mixture of suchsolvents.

The reaction is conducted by using from 1 to 2 mols of such anucleophilic reagent relative to one mol of the compound of the formulaII-1 at a reaction temperature of from -20° to 40° C. for a reactiontime of from 0.5 to 5 hours.

Further, when Q² in the formula II-1 is an acetoxy group, the reactionwith said nucleophilic agent can be conducted in water, a phosphatebuffer or an organic solvent such as acetone, acetonitrile, methanol,ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide ordimethylsulfoxide or in a mixture of such solvents. The reaction ispreferably conducted under a nearly neutral condition. The reactiontemperature is from room temperature to 90° C., and the reaction time isfrom 1 to 15 hours. This reaction is facilitated by conducting it in thepresence of an iodide compound such as sodium iodide or potassiumiodide, a thiocyanate such as sodium thiocyanate or potassiumthiocyanate, and a quaternary ammonium salt such astrimethylbenzylammonium bromide.

The sulfoxide group of the compound of the formula II-1 or II-2 whereingroup Y is SO, can be reduced in accordance with the methods disclosedin Journal of Organic Chemistry, Vol. 35, p.2430 (1974) and the like.For example, it may be mentioned that the compound of the formula II-1or II-2 wherein group Y is SO can be reduced by phosphorus trichlorideor acetyl chloride/sodium iodide. Namely, the compound of the formulaII-1 or II-2 wherein group Y is SO, can be reduced by reacting it withphosphorus trichloride in a solvent such as N,N-diemthylformamide at atemperature of from -40° to 0° C. for from 1 to 5 hours. The reaction isconducted by using from 2 to 6 mols of phosphorus trichloride relativeto one mol of the compound of the formula II-1 or II-2.

Or, the compound of the formula II-1 or II-2 wherein group Y is SO, canbe reduced by a dropwise addition of acetyl chloride in an acetonesolvent in the presence of sodium iodide or an idodide compound at atemperature of from -40° to 0° C. for from 1 to 5 hours for reaction.The reaction is conducted by using from 3.5 to 10 mols of an iodidecompound and from 1.2 to 5 mols of acetyl chloride relative to one molof the compound of the formula II-1 or II-2 wherein group Y is SO. Thecompound of the formula I of the present invention can be prepared byoptionally removing the protecting group from the compound of theformula II-1 or II-2 wherein group Y is S.

As the protecting groups for the carboxyl, amino and hydroxyl groups inthe above formulas, protecting groups which are commonly employed in thefield of β-lactam synthesis, may suitably be selected. The introductionand removal of the protecting groups may be conducted in accordance withthe methods disclosed in, for instance, "Protective Groups in OrganicSynthesis" written by T. W. Greene published in 1981 by Wiley Companyand in "Protective Groups in Organic Chemistry" written by J. F. W.McOmie published in 1973 by Plenuum Press.

As the carboxyl-protecting group, there may be mentioned, for example, atert-butyl group, a 2,2,2-trichloroethyl group, an acetoxymethyl group,a propionyloxymethyl group, a pivaloyloxymethyl group, a 1-acetoxyethylgroup, a 1-propionyloxyethyl group, a 1-(ethoxycarbonyloxy)ethyl group,a phthalidyl group, a benzyl group, a 4-methoxybenzyl group, a3,4-dimethoxybenzyl group, a 4-nitrobenzyl group, a benzhydryl group, abis(4-methoxyphenyl)methyl group, a(5-methyl-2-oxo™1,3-dioxol-4-yl)methyl group, a trimethylsilyl group ora tert-butyldimethylsilyl group. Partiularly preferred are a benzhydrylgroup, a tert-butyl group and a silyl group.

As the amino-protecting group, there may be mentioned, for example, atrityl group, a formyl group, a chloroacetyl group, a trifluoroacetylgroup, a tert-butoxycarbonyl group, a trimethylsilyl group or atert-butyldimethylsilyl group.

As the hydroxyl-protecting group, there may be mentioned, for example, a2-methoxyethoxymethyl group, a methoxymethyl group, a methylthiomethylgroup, a tetrahydropyranyl group, a phenacyl group, an isopropyl group,a tert-butyl group, a benzyl group, a 4-nitrobenzyl group, an acetylgroup, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group,a trimethylsilyl group or a tert-butyldimethylsilyl group, or a cyclicacetal such as methylene acetal, ethylene acetal or benzylidene acetal,an orthoester such as methoxymethylidene or methoxyethylidene, a cyclicketal such as isopropylidene ketal or a cyclic carbonate, which isformed by the combination of protecting groups each other.

The removal of the protecting group may be conducted by employing asuitable method selected from usual methods depending upon the type ofthe protecting group. For instance, the removal of a protecting groupsuch as a trityl group, a formyl group, a tert-butoxycarbonyl group, abenzhydryl group, a tert-butyl group or a 2-methoxyethoxymethyl group,may be conducted by means of an inorganic or organic acid such ashydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonicacid or p-toluenesulfonic acid. Trifluoroacetic acid is particularlypreferred. When trifluoroacetic acid is used as the acid, the reactioncan be facilitated by an addition of anisole, thioanisole or phenol, andside reactions can be thereby suppressed. The reaction may be conductedin a solvent which does not adversely affect the reaction, such aswater, methylene chloride, chloroform, ethylene chloride or benzene, orin a mixture of such solvents. The reaction temperature and time aresuitably selected depending upon the chemical properties of the compoundof the formula II-1 or II-2 and that of the compound of the formula I ofthe present invention, and the type of the protecting group. Thereaction is preferably conducted under a mild condition ranging from anice-cooling condition to a slightly heated condition.

The compound of the formula IV or II-1 wherein group Y is SO, can beprepared by oxidizing the compound of the formula IV or II-1 whereingroup Y is S, with m-chloroperbenzoic acid, hydrogene peroxide ormetaperiodic acid in an organic solvent inert to the reaction such asmethylene chloride, ethylene chloride, chloroform, diethyl ether oracetic acid at a temperature of from ice-cooling to room temperature(the Journal of Organic Chemistry, Vol. 35, p. 2430 .(1970)).

The compound of the formula IV wherein group Y is an idodine atom, canbe prepared by reacting the compound of the formula II-1 wherein groupQ² is a chlorine atom with an iodide compound such as sodium idodide ina solvent such as acetone or N,N-dimethylformamide at a temperature offrom ice-cooling to room temperature (e.g. Japanese Examined PatentPublication No. 27679/1976 or Synthetic Communications, Vol. 16,p.1029-1035 (1986)). The product may be used for the subsequent reactionwithout or after isolation.

Further, the compound of the formula IV can be prepared in accordancewith the methods disclosed in "Cephalosporins and Penicillins",p.151-171 and 675 written by Flynn published in 1972 by Academic Press,"Journal of Organic Chemistry", Vol. 32, p.500 (1967) and JapaneseUnexamined Patent Publication No. 154786/1979. For instance, a7β-amino-3-chloromethyl-3-cephem-4-carboxylic acid derivative (e.g.prepared in accordance with the method disclosed in Japanese UnexaminedPatent Publication-2-6 No. 76089/1975 or No. 86178/1981), a7β-acylamino-3-halomethyl-3-cephem-4-carboxylic acid derivative (e.g.prepared in accordance with the method disclosed in Japanese UnexaminedPatent Publication No. 72590/1983 or No. 154588/1983), a7β-aminocephalosporanic acid or a 7β-acylaminocephalosporanic acidderivative, is reacted with the above nucleophilic reagent to obtain acompound having the formula: ##STR11## wherein R² is a hydrogen atom, acarboxyl-protecting group or a negative charge, R⁸ is a hydrogen atom oran acyl group, Q² is a hydrogen atom, a halogen atom, a hydroxyl group,an acetoxy group, a carbamoyloxy group, an azide group, a substituted orunsubstituted quarternary ammonio group or a substituted orunsubstituted heterocyclic thio group having at least one hetero atomselected from the group consisting of a nitrogen atom, an oxygen atom ora sulfur atom, and Y is S or SO, provided that Q² and a substituentthereof may be protected, optionally followed by deacylation.

The deacylation reaction is commonly known in this field. For example,there is a method comprising iminochlorination by phosphoruspentachloride or the like, followed by iminoetherification with methanolor the like and hydrolysis (e.g. Japanese Examined Patent publicationNo. 20319/1974) or a method by an acylase (e.g. Japanese Examined PatentPublication No. 291431/1986).

As an acyl group, for example, a phenylacetyl group, a phenoxyacetylgroup or an aminoadipyl group may be mentioned.

Now, the process for producing the compound of the formula III which isthe second object of the present invention, which is useful as anintermediary material of the compound of the present invention, will beexplained.

The compound of the formula III can be prepared by reacting a compoundhaving the formula: ##STR12## wherein R⁶ is a hydrogen atom or anamino-protecting group and R⁷ is a hydrogen atom or acarboxyl-protecting group, with a compound having the formula: ##STR13##wherein R⁸ is a hydrogen atom or a carboxyl-protecting group, optionallyfollowed by removal of the protecting groups.

The reaction of the compound of the formula VI with the hydroxylaminederivative of the formula V, is conducted by using from 1.0 to 1.5 molsof the compound of the formula V relative to one mol of the compound ofthe formula VI in a suitable solvent which does not adversely affect thereaction, such as water, methanol, ethanol, tetrahydrofuran,N,N-dimethylformamide or dimethylsulfoxide, or a mixture of such anorganic solvent with water, at a reaction temperature of from 5° to 70°C. for a reaction time of from 0.5 to 5 hours, whereby the reaction iscompleted.

After completion of the reaction, if necessary, the removal of theprotecting groups of the compound of the present invention may beconducted by employing a suitable method selected from those usuallyused in the field of the organic sysnthesis chemistry. The removal ofthe protecting group can be conducted in accordance with a methoddisclosed in e.g. "Protective Groups in Organic Synthesis", written byT. W. Green published in 1981 by Wiley Company or in "Protective Groupsin Organic Chemistry" written by J. F. W. McOmie published in 1973 byPlenum Press. Particularly preferred protecting group is one which canreadily be removed by a usual method such as acid treatment, hydrolysisor reduction.

For instance, when the amino-protecting group for R⁶ is a formyl group,a benzhydryl group, a trityl group or a tert-butoxycarbonyl group,and/or each of the carboxyl-protecting groups for R⁷ and R⁸ which may bethe same or different is a tert-butyl group or a benzhydryl group, theprotecting group can be removed by treating the compound of the formulaIII of the present invention with an inorganic or organic acid such ashydrochloric acid, formic acid, trifluoroacetic acid, benzenesulfonicacid or p-toluenesulfonic acid. Particularly preferred istrifluoroacetic acid. When trifluoroacetic acid is used as the acid, thereaction can be facilitated by an addition of anisole, thioanisole orphenol, and side reactions can be thereby suppressed. The reaction maybe conducted by using from 0.1 to 20 equivalent times (V/W), preferablyfrom 0.5 to 10 equivalent times (V/W) of the acid relative to oneequivalent of the compound of the present invention in a solvent whichdoes not adversely affect the reaction, such as water, methylenechloride, chloroform, ethylene chloride or benzene, or in a mixture ofsuch solvents. The reaction may be conducted under a mild conditionranging from an ice-cooling condition to a slightly heated condition.For instance, when the amino-protecting group for R⁶ is atrifluoroacethyl group, a trimethylsilyl group, and/or each of thecarboxyl-protecting groups for R⁷ and R⁸ which may be the same ordifferent, is a methyl group, an ethyl group, a propyl group, anisopropyl group, a tert-butyl group, a benzyl group or benzhydryl group,the protecting group of the compound of the formula III of the presentinvention can be removed by, for example, hydrolysis with an alkali oran acid. As such an alkali, there may be mentioned an alkali metalhydroxide such as sodium hydroxide or potassium hydroxide, or an alkalimetal carbonate such as sodium carbonate or potassium carbonate. As suchan acid, for example, hydrochloric acid, hydrobromic acid or dilutedsulfuric acid may be mentioned. The reaction is conducted by using from0.5 to 5 equivalent mol, preferably from 1 to 3 equivalent of the baseor from 0.1 to 20 times (V/W), preferably from 0.5 to 10 times (V/W) ofthe acid relative to one equivalent of the compound of the presentinvention in a solvent such as water, methanol, ethanol, tetrahydrofuranor dioxane, or in a mixture of such solvents, and the reactiontemperature is from 0° to 80° C.

For instance, when the amino-protecting group for R⁶ is abenzyloxycarbonyl group, and/or each of the carboxyl-protecting groupsfor R⁷ and R⁸ which may be the same or different, is a benzyl group, a4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a 4-nitrobenzylgroup or a benzhydryl group, the protecting group can be removed byconducting a catalytic reduction of the compound of the formula III ofthe present invention under a hydrogen gas stream in the presence of acatalyst such as palladium black under an atomspheric pressure to anelevated pressure at a temperature of from 10° to 70° C. As the solventfor the reaction, for example, water, methanol, ethanol ortetrahydrofuran, or a mixture of such organic solvents and water may beemployed.

After completion of the reaction, the isolation and purification of thecompound of the formula III of the present invention or its salt fromthe reaction solution, can be conducted by means of a separation methodsuch as extraction with a solvent, recrystallization or chromatography.Further, the compound of the formula III of the present invention can beconverted to an addition salt with a base or an acid, or a solvate witha suitable solvent by a usual method.

As the addition salt of the compound of the formula III of the presentinvention with the base, there may be mentioned a salt of an alkalimetal such as sodium or potassium, a salt of an alkali earth metal suchas calcium or magnesium, or a salt of an amine such as ammonium,trimethylamine, triethylamine, dicyclohexylamine,N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine,triethanolamine, procaine, pyridine, picoline, quinoline orisoquinoline. Further, as the addition salt with an acid, there may bementioned a salt of an inorganic acid such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, carbonicacid, hydrogencarbonic acid or perchloric acid, a salt of an organicacid such as acetic acid, propionic acid or trifluoroacetic acid, a saltof a sulfonic acid such as methanesulfonic acid, isethionic acid,benzenesulfonic acid or p-toluenesulfonic acid, or a salt of an aminoacid such as arginine or lysine.

As the solvent forming the solvate with the compound of the formula IIIof the present invention, there may be mentioned, for example, water,methanol, ethanol, propanol, glycol, methylcellosolve, acetone,acetonitrile, tetrahydrofuran, dioxane, benzene, toluene, xylene,methylene chloride, chloroform, carbon tetrachloride, ethylene chloride,formamide, N,N-dimethylformamide, acetamide, N,N-dimeth-ylacetamide ordimethylsulfoxide.

The starting material compound of the formula III of the presentinvention can be prepared in accordance with the method disclosed, forexample, in Journal of the Japanese Chemical Society, p.785-801 (1981).

Further, the starting material compound of the formula VIII is a novelcompound and can be prepared in accordance with, for example, thefollowing reaction scheme. ##STR14## In the formulas, R⁸ is a hydrogenatom or a carboxyl-protecting group.

Namely, the compound of the formula VII can be prepared by reacting aN-(1-carboxy-1-vinyloxy)phthalimide derivative of the formula VIIIobtained in accordance with the method disclosed in the specification ofBritish Patent No. 1,602,725, with hydrazine in an amount of from 1.0 to2.5 mols relative to one mol of the compound of the formula VIII in asolvent such as methanol, ethanol, methylene chloride, ethylenechloride, tetrahydrofuran, N,N-dimethylformamide or dimethylsulfoxide ata reaction temperature of from -5° to 40° C. The product can be used forthe subsequent reaction after or without isolation.

Now, the in vitro antibacterial activities of the compounds of thepresent invention against various microorganisms, were measured by thefollowing agar plate dilution method.

One platinum loopfull of each test microorganism incubated overnight inMueller Hinton broth, was inoculated to Mueller Hinton agar (MH agaer).Such culture media containing various antibiotics in variousconcentrations were prepared. After incubation at 37° C. for 16 hours,the minimum inhibitory concentrations (MIC μg/ml) were measured. Theresults are shown in the following Table.

    __________________________________________________________________________    Tested compound                                                               Test microorganism                                                                            MIC (μg/ml: 10.sup.6 CFU/ml)                                 (*β-Lactamase-producing                                                                Example                                                                             Example                                                                            Example                                                                             Example                                                                             Example                                                                            Example                                                                              Example                                                                             Example                strain)       1     2    3     4     5    6      7     8                    __________________________________________________________________________      S. aureus 209P NIHJ-JC1                                                                     3.12  1.56 6.25  1.56  12.5 1.56   25    6.25                   E. coli NIHJ JC2                                                                            0.025 0.05 0.2   0.05  0.2  0.05   0.1   0.05                   E. coli CSH2(RK1)*                                                                          0.0125                                                                              0.025                                                                              0.05  0.025 0.2  0.025  0.2   0.05                   K. pneumoniae PC1-602                                                                       <0.006                                                                              0.0125                                                                             0.025 0.0125                                                                              0.025                                                                              <0.006 0.025 0.025                  E. coli CSH(RE45)*                                                                          0.025 0.78 0.05  0.025 0.05 0.025  0.05  0.05                   K. oxytoca GN10650*                                                                         0.1   0.1  0.2   0.1   0.39 0.2    0.39  0.2                    K. pneumoniae No. 42*                                                                       0.1   0.39 0.39  0.1   0.39 0.1    0.39  0.39                   P. vulgaris HX-19                                                                           0.0125                                                                              0.025                                                                              0.0125                                                                              0.0125                                                                              <0.006                                                                             0.0125 0.0125                                                                              0.025                  P. vulgaris No. 33*                                                                         0.0125                                                                              0.025                                                                              0.05  0.0125                                                                              0.0125                                                                             0.0125 0.0125                                                                              0.05                 10.                                                                             S. marcescens IAM 1184                                                                      <0.006                                                                              0.0125                                                                             0.05  0.0125                                                                              0.025                                                                              <0.006 0.0125                                                                              0.025                  E. cloacae 963                                                                              0.025 0.05 0.1   0.05  0.2  0.05   0.1   0.2                    E. cloacae Nek 39*                                                                          0.39  0.2  3.12  0.2   3.12 1.56   3.12  0.78                   E. coli GN5482*                                                                             0.2   0.1  3.12  0.2   1.56 0.39   1.56  0.39                   M. morganii GN5407*                                                                         0.0125                                                                              0.025                                                                              0.05  0.0125                                                                              0.025                                                                              0.025  0.025 0.05                   S. marcescens No. 16-2*                                                                     0.78  0.78 3.12  0.78  6.25 3.12   3.12  3.12                   Ps. aeruginosa IFO3445                                                                      0.78  1.56 6.25  1.56  25   6.25   3.12  3.12                   Ps. aeruginosa AK 109                                                                       1.56  1.56 100   12.5  25   12.5   25    12.5                   Ps. aeruginosa AKR17                                                                        >100  100  >100  >100  >100 >100   >100  >100                   Ps. cepacia 23                                                                              3.12  0.39 6.25  3.12  12.5 3.12   12.5  12.5                 20.                                                                             A. calcoaceticus No. 4                                                                      12.5  3.12 25    3.12  50   12.5   50    12.5                 __________________________________________________________________________    Tested compound                                                               Test microorganism                                                                            MIC (μg/ml: 10.sup.6 CFU/ml)                                 (*β-Lactamase-producing                                                                Example                                                                              Example                                                                             Example                                                                            Example                                                                             Example                                                                            Example                                                                             Example                                                                             Example                strain)       9      10    11   12    13   14    15    16                   __________________________________________________________________________      S. aureus 209P NIHJ-JC1                                                                     3.12   1.56  12.5 3.12  3.12 6.25  25    12.5                   E. coli NIHJ JC2                                                                            0.025  0.0125                                                                              0.05 0.39  0.2  0.78  0.39  0.78                   E. coli CSH2(RK1)*                                                                          0.025  0.0125                                                                              <0.006                                                                             0.025 <0.006                                                                             0.0125                                                                              0.0125                                                                              0.05                   K. pneumoniae PC1-602                                                                       <0.006 <0.006                                                                              <0.006                                                                             <0.006                                                                              0.0125                                                                             <0.006                                                                              <0.006                                                                              <0.006                 E. coli CSH(RE45)*                                                                          0.0125 0.0125                                                                              0.05 0.025 <0.006                                                                             0.025 0.05  1.56                   K. oxytoca GN10650*                                                                         0.1    0.05  0.025                                                                              0.1   0.025                                                                              0.1   0.1   0.1                    K. pneumoniae No. 42*                                                                       0.1    0.05  0.025                                                                              0.05  0.0125                                                                             0.05  0.1   0.1                    P. vulgaris HX-19                                                                           0.0125 <0.006                                                                              <0.006                                                                             <0.006                                                                              <0.006                                                                             <0.006                                                                              0.0125                                                                              <0.006                 P. vulgaris No. 33*                                                                         0.0125 0.0125                                                                              0.0125                                                                             0.025 0.025                                                                              0.025 <0.006                                                                              0.025                10.                                                                             S. marcescens IAM 1184                                                                      <0.006 <0.006                                                                              0.025                                                                              0.05  0.025                                                                              0.05  0.05  0.05                   E. cloacae 963                                                                              0.05   0.025 0.025                                                                              0.2   0.05 0.39  0.05  0.39                   E. cloacae Nek 39*                                                                          0.78   0.39  0.025                                                                              0.1   0.05 0.1   0.05  0.2                    E. coli GN5482*                                                                             0.2    0.1   0.1  0.39  0.2  1.56  0.39  0.78                   M. morganii GN5407*                                                                         0.39   0.0125                                                                              0.0125                                                                             0.05  0.1  0.05  0.025 0.05                   S. marcescens No. 16-2*                                                                     1.56   1.56  0.2  0.39  0.05 0.39  0.78  0.78                   Ps. aeruginosa IFO3445                                                                      0.78   0.78  0.39 0.78  0.78 0.78  1.56  0.78                   Ps. aeruginosa AK 109                                                                       3.12   3.12  0.2  1.56  0.1  0.78  0.78  0.78                   Ps. aeruginosa AKR17                                                                        >100   >100  3.12 3.12  1.56 3.12  1.56  1.56                   Ps. cepacia 23                                                                              3.12   3.12  <0.006                                                                             0.025 <0.006                                                                             0.0125                                                                              <0.006                                                                              <0.006               20.                                                                             A. calcoaceticus No. 4                                                                      3.12   3.12  0.1  0.2   0.1  0.2   0.39  0.2                  __________________________________________________________________________                 Tested compound                                                               Test microorganism                                                                          MIC (μg/ml: 10.sup.6 CFU/ml)                                 (*β-Lactamase-producing                                                                Example                                                                             Example                                                                             Example                                                                             Example                                                                             Ceftazi-                                strain)       17    18    19    20    dime  Cefotaxime           __________________________________________________________________________               1.                                                                              S. aureus 209P NIHJ-JC1                                                                     12.5  3.12  6.25  25    6.25  1.56                            2.                                                                              E. coli NIHJ JC2                                                                            0.1   0.2   0.05  0.39  0.1   0.05                            3.                                                                              E. coli CSH2(RK1)*                                                                          0.025 0.025 0.025 0.2   .1    0.0125                          4.                                                                              K. pneumoniae PC1-602                                                                       0.0125                                                                              0.025 0.0125                                                                              0.1   0.25  <0.006                          5.                                                                              E. coli CSH(RE45)*                                                                          0.1   0.1   0.1   0.78  0.2   0.1                             6.                                                                              K. oxytoca GN10650*                                                                         0.05  0.2   0.05  0.39  0.1   0.39                            7.                                                                              K. pneumoniae No. 42*                                                                       0.2   0.39  0.2   0.78  0.39  0.05                            8.                                                                              P. vulgaris HX-19                                                                           <0.006                                                                              <0.006                                                                              <0.006                                                                              <0.006                                                                              0.025 <0.006                          9.                                                                              P. vulgaris No. 33*                                                                         0.1   <0.006                                                                              <0.006                                                                              <0.006                                                                              0.5   0.025                           10.                                                                             S. marcescens IAM 1184                                                                      0.0125                                                                              0.025 <0.006                                                                              0.05  <0.006                                                                              0.0125                          11.                                                                             E. cloacae 963                                                                              0.1   0.2   0.1   0.39  0.1   0.05                            12.                                                                             E. cloacae Nek 39*                                                                          3.12  0.78  0.78  3.12  1.56  1.56                            13.                                                                             E. coli GN5482*                                                                             1.56  0.39  0.39  1.56  1.56  0.39                            14.                                                                             M. morganii GN5407*                                                                         0.025 0.0125                                                                              0.025 0.05  0.1   0.05                            15.                                                                             S. marcescens No. 16-2*                                                                     3.12  3.12  1.56  3.12  1.56  6.25                            16.                                                                             Ps. aeruginosa IFO3445                                                                      6.25  12.5  6.25  6.25  1.56  25                              17.                                                                             Ps. aeruginosa AK 109                                                                       6.25  12.5  6.25  12.5  0.78  12.5                            18.                                                                              Ps. aeruginosa AKR17                                                                       >100  >100  >100  >100  >100  >100                            19.                                                                             Ps. cepacia 23                                                                              1.56  3.12  3.12  3.12  0.78  6.25                            20.                                                                             A. calcoaceticus No. 4                                                                      25    100   100   100   6.25  25                   __________________________________________________________________________

Further, the compounds of the present invention exhibit excellentpharmacokinetics. As a representative example, the compound of Example15 was administered to mice by means of subcutaneous administration, andthe concentration in the blood was measured.

Four week old ddY type male mice (weight: 19-22 g) were used in a groupof 5 animals. The test compound was dissolved in a physiological sodiumchloride solution to obtain a formulation having a concentration of 2mg/ml. The formulation was subcutaneously administered to the mice in anamount of 0.1 ml per 10 g of the weight of the mice. 7.5, 15, 30, 60,120 and 240 minutes after the administration, the blood was sampled fromthe heart of mice by means of a syringe treated with heparin. Theconcentration in the blood at each measurement is shown in the followingTable.

Now, Ceftazidime was used as a comparative compound. Further, theantibacterial activities of the sample diluted by plasma to have anappropriate concentration were measured by the paper disk method usingMorganella morganii IFO 3843 as the test bacterium.

As is evident from the results in the following Table, the compound ofthe present invention can promptly reach a high concentration in theblood and excellent as compared with that of Ceftazidime.

    ______________________________________                                        Concentration in blood                                                                     Period after administration                                              Dose   7.5    15     30   60   120  240                               Test compound                                                                           (mg/kg)  (min.)                                                     ______________________________________                                        Example 15                                                                              20       33.8   45   44.3 21.9 7.1  7.2                             Ceftazidime                                                                             20       25.4   24.1 17.3 3.3  0.2  --                              ______________________________________                                         (Unit: μg/ml)                                                         

The compounds of the present invention exhibit strong antibacterialactivities against Gram-positive and Gram-negative bacteria andparticularly excellent activities against resistant Gram-negativebacteria including Pseudmonas aeruginosa. Thus, the compounds of theformula I and non-toxic salts and their physiologically hydrolyzablenon-toxic esters thereof are useful as antibacterial agents.

The compounds of the present invention may be mixed with a carrier ofsolid or liquid excipient which is known in this field, and may be usedin the form of a pharmaceutical formulation suitable for parenteraladministration, oral administration or external administration.

As the pharmacetical formulations, there may be mentioned liquidformulations such as injection solutions, syrups and emulsions, solidformulations such as tablets, capsules and granules and formulations forexternal application such as ointments and suppositories. Further, theseformulations may optionally contain commonly employed additives such asassisting agents, stabilizers, wetting agents, emulsifying agents,absorption-promoting agents or surfactants. As such additives, distilledwater for injection, a Ringer solution, glucose, sucrose syrup, gelatin,edible oil, coconut oil, ethylene glycol, sucrose, corn starch,magnesium stearate and talc, may be mentioned.

Further, the compounds of the present invention can be used asantibacterial agents for the treatment of human infectious deseases.

The dose may vary depending upon the condition such as the age or sex ofthe patient, and is usually within a range of from 1 to 100 mg/kg perday. It is preferred to administer a daily dose of from 5 to 30 mg/kg in2 to 4 times.

Now, the present invention will be described in further detail withreference to Examples and Reference Examples. However, the presentinvention is by no means restricted thereto.

EXAMPLES Example 1 Preparation of7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate(syn-isomer)

(A) 5.06 g (9.76 mmol) of 2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) and 4.05 g (9.76mmol) of benzhydryl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate weredissolved in 100 ml of methylene chloride, and 5.56 ml (43.9 mmol) ofN,N-dimethylaniline and 1.07 ml (11.5 mmol) of phosphorus oxychloridewere dropwise added thereto at 0° C. The mixture was stirred for onehour. The reaction solution was washed sequentially with 0.5Nhydrochloric acid and with a saturated sodium chloride aqueous solution.The extracted solution was dried over anhydrous sodium sulfate, and thenthe solvent was distilled off under reduced pressure to obtain 8.7 g(yield: 96.7%) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn-isomer).

IR(KBr)cm⁻¹ : 3400, 2960, 1790, 1720, 1520, 1150, 700

NMR(DMSO-d₆)δ: 1.48(9H, s), 3.47 and 3.75(2H, ABq, J=18Hz), 4.45(2H, brs), 5.19(1H, br s), 5.27(1H, d, J=4.5Hz), 5.35(1H, br s), 5.77(1H, dd,J=4.5 and 7.5 Hz), 6.92(1H, s), 6.95(1H, s), 7.30(25H, m), 8.86(1H, brs), 9.79(1H, d, J=7.5Hz)

(B) 4 g (4.34 mmol) of the compound obtained in the above reaction (A)was dissolved in 80 ml of acetone, and 3.25 g (21.7 mmol) of sodiumiodide was added thereto. The mixture was stirred at room temperaturefor one hour. The solvent was distilled off under reduced pressure. Tothe residue, 80 ml of ethyl acetate was added, and the mixture waswashed sequentially with water, with a 10% sodium thiosulfate aqueoussolution and with a saturated sodium chloride aqueous solution. Theextracted solution was dried over anhydrous sodium sulfate. Then, thesolvent was distilled off under reduced pressure, and the residue waswashed with diisopropyl ether to obtain 3.98 g (yield: 90.5%) ofbenzhydryl7B-[2-(tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]3-iodomethyl-3-cephem-4-carboxylate(syn-isomer).

(C) 304 mg (0.3 mmol) of the compound obtained in the above reaction (B)was dissolved in 6 ml of N,N-dimethylformamide, and 0.03 ml (0.36 mmol)of pyridine was added thereto. The mixture was stirred at roomtemperature for one hour. The solvent was distilled off under reducedpressure, and the residue was subjected to silica gel columnchromatography (Wakogel C-300). The eluted fraction (8%methanol/chlorform) was concentrated to obtain 230 mg (yield: 85.4%) ofbenzhydryl 7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-20tritylaminothiazol-4-yl)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylateiodide (syn-isomer) as foamy substance.

(D) 280 mg (0.26 mmol) of the compound obtained in the above reaction(C) was dissolved in 4 ml of methylene chloride and 0.8 ml of anisole,and 8 ml of trifluoroacetic acid was added thereto under cooling withice. The mixture was stirred for one hour. The solvent was distilledoff, and to the residue, diethyl ether was added. The precipitates werecollected by filtration. The precipitates were dissolved in 50 ml of a10% methanol aqueous solution. Then, the solution was subjected to ODScolumn chromatography (LC-Sorb RP-18, Kemco Co.), and eluted with a 20%methanol aqueous solution. The eluted fraction containing the desiredcompound was concentrated and freeze-dried to obtain 70 mg (yield: 50%)of the above identified compound.

mp: 150° C. (decomposed)

IR(KBr)cm⁻ : 3420, 1780, 1630, 1540, 1395, 1200

NMR(DMSO-d6/D2O)δ: 2.90-3.60(2H, ABq), 5.06(1H, d,J=4,5Hz),,5.20-5.50(4H, m), 5.70(2H, d, J=4.5Hz), 6.95(1H, s), 7.95(2H,m), 8.40(1H, m), 8.90(1H, m)

Example 2 Preparation of7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(2,3-cychlopenteno-pyridinio)methyl-3-cephem-4-carboxylate(syn-isomer)

The same operations as in the steps (C) and (D) of Example 1 wereconducted by using 234 mg (0.28 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate(syn-isomer) and 0.033 ml (0.28 mmol) of 2,3-cyclopentenopyridine. Theproduct was subjected to ODS column chromatography and eluted with a 20%methanol aqueous solution to obtain 45 mg (yield: 28.1%) of theabove-identified compound.

mp: 150° C. (decomposed)

IR(KBr)cm-¹ : 3420, 1770, 1620, 1540, 1400, 1200

NMR(DMSO-d₆ /D₂ O)δ: 2.15(2H, m), 2.80-3.30(6H, m), 5.05(2H, d,J=4.5Hz), 5.10-5.30(4H, m), 5.66(1H, d, J=4.5Hz), 6.93(1H, s), 7.60(1H,m), 8.15(1H, d, J=8Hz), 8.45(1H, d, J=8Hz)

Example 3 Preparation of7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylate(syn-isomer)

The same operations as in steps of (C) and (D) of Example 1 wereconducted by using 305 mg (0.3 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate(syn-isomer) and 95.6 mg (0.31 mmol) of benzhydryl nicotinate. Theproduct was subjected to ODS column chromatography and eluted with a 20%methanol aqueous solution to obtain 31 mg (yield: 18.0%) of theabove-identified compound.

mp: 130° C. (decompoed)

IR(KBr)cm⁻¹ : 3400, 1770, 1640, 1620, 1390, 1200

NMR(DMSO-d₆ /D₂ O)δ: 3.10-3.80(2H, ABq), 5.10(1H, d, J=4.5Hz),5.25-5.50(4H, m), 5.70(1H, d, J=4.5Hz), 6.93(1H, s), 8.00(1H, m),8.70(1H, br s), 8.95(1H, br s), 9.25(1H, s)

Example 4 Preparation of7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]vinyloxyimino)acetamido]-3-(3-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate(syn-isomer)

The same operations as in steps of (C) and (D) of Example 1 wereconducted by using 305 mg (0.3 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate(syn-isomer) and 38.4 mg (0.31 mmol) of nicotinamide. The product wassubjected to ODS column chromatography and eluted with a 20% methanolaqueous solution to obtain 55.8 mg (yield: 32.4%) of theabove-identified compound.

mp: 150° C. (decompoed)

IR(KBr)cm⁻¹ : 1 3400, 1780, 1680, 1620, 1400, 1200

NMR(DMSO-d₆ /D₂ O)δ: 3.10-3.80(2H, ABq), 5.20(1H, d, J=4.5Hz),5.40-5.60(4H, m), 5.83(1H, d, J=4.5Hz), 7.06(1H, s), 8.21(1H, m),8.90(1H, br s), 9.20(1H, br s), 9.45(1H, s)

Example 5 Preparation of7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carboxy-1-pyridinio)methyl-3-cephem-4-carboxylate(syn-isomer)

The same operations as in steps of (C) and (D) of Example 1 wereconducted by using 203 mg (0.2 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate(syn-isomer) and 203 mg (0.2 mmol) of benzhydryl isonicotinate. Theproduct was subjected to ODS column chromatography and eluted with a 20%methanol aqueous solution to obtain 36 mg (yield: 31.3%) of theabove-identified compound.

mp: 150° C. (decomposed)

IR(KBr)cm : 3420, 1780, 1630, 1380, 1200

NMR(DMSO-d₆ /D₂ O)δ: 3.10-3.75(2H, ABq), 5.22(1H, d, J=4.5Hz),5.40-5.70(4H, m), 5.85(1H, d, J=4.5Hz), 7.10(1H, s), 8.30(2H, d, J=6Hz),9.05(2H, d, J=6Hz)

Example 6 Preparation of7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate(syn-isomer)

The same operations as in the steps of (C) and (D) of Example 1 wereconducted by using 203 mg (0.2 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate(syn-isomer) and 25.6 mg (0.21 mmol) of isonicotinamide. The product wassubjected to ODS column chromatography and eluted with a 20% methanolaqueous solution to obtain 31 mg (yield: 27.0%) of the above-identifiedcompound.

mp: 160° C. (decomposed)

IR(KBr)cm⁻¹ : 3420, 1780, 1670, 1630, 1540, 1400, 1350, 1200

NMR(DMSO-d₆ D₂ O)δ: 3.10-3.70(2H, ABq), 5.10(1H, d, J=4.5Hz),5.30-5.55(4H, m), 5.75(1H, d, J=4.5Hz), 7.00 (1H, s), 8.30(2H, d,J=6Hz), 9.10(2H, d, J=6Hz)

Example 7 Preparation of7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino]acetamido]-3-(4-sulfonatomethyl-1-pyridinio)methyl-3-cephem-4-carboxylicacid (syn-isomer)

(A) 773 mg (0.75 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate1-oxide (syn-isomer) was dissolved in 5 ml of N,N-dimethylformamide, and293 mg (1.5 mmol) of potassium 4-pyridylmethanesulfonate was addedthereto. The mixture was left to stand at room temperature for 2 hours.The solvent was distilled off under reduced pressure, and the residuewas subjected to silica gel column chromatography (Wakogel C-300) toobtain 650 mg (yield: 70.7%) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(4-sulfonatomethyl-1-pyridinio)methyl-3-cephem-4-carboxylate1-oxide (syn-isomer) as foamy substance. (B) 650 mg (0.53 mmol) of thecompound obtained in the above reaction (A) was dissolved in 4 ml ofN,N-dimethylformamide, and 0.13 ml (1.5 mmol) of phosphorus trichloridewas added thereto at -40° C. The reaction solution was stirred at atemperature of from -20 poured into ice water, and the precipitates werecollected by filtration. This precipitates were dissolved in methylenechloride, and the solution was dried over anhydrous sodium sulfate.Then, the solvent was distilled off under reduced pressure to obtain 510mg (yield: 79.5%) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido-3-(4-sulfonatomethyl-1-pyridinio)methyl-3-cephem-4-carboxylate(syn-isomer). The product was used for the subsequent reaction withoutpurification.

(C) 500 mg (0.41 mmol) of the compound obtained in the above reaction(B) was subjected to the same operation as in step of (D) of Example 1.The product was subjected to ODS column chromtography and eluted with a20% methanol aqueous solution to obtain 94.2 mg (yield: 35.7%) of theabove-identified compound.

mp: 130° C. (decomposed)

IR(KBr)cm⁻¹ : 3450, 1780, 1640, 1400, 1200, 1040

NMR(DMSO-d₆ /D₂ O)δ: 3.20-3.60(2H, ABq), 4.20(2H, s), 5.20(1H, d,J=4.5Hz), 5.30-5.60(4H, m), 5.86(1H, d, J=4.5Hz), 7.00(1H, s), 8.05(2H,d, J=6Hz), 8.90(2H, d, J=6Hz)

Example 8 Preparation of7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[4-(2-sulfonatoethyl)-1-pyridinio]methyl-3-cephem-4-carboxylicacid (syn-isomer)

The same operation as in Example 7 was conducted by using 773 mg (0.75mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate1-oxide (syn-isomer) and 328 mg (1.5 mmol) of potassium2-(4-pyridyl)ethanesulfonate. The product was subjected to ODS columnchromatography and eluted with a 20% methanol aqueous solution to obtain76 mg of the above-identified compound.

mp: 130° C. (decomposed)

IR(KBr)cm⁻¹ : 3450, 1780, 1630, 1520, 1400, 1200

NMR(DMSO-d₆ /D₂ O)δ: 3.20-3.16(2H, ABq), 3.30-3.70(4H, m), 5.20(1H, d,J=4.5Hz), 5.30-5.60(4H, m), 5.75(1H, d, J=4.5Hz), 6.96(1H, s), 8.15(2H,d, J=6Hz), 9.10(2H, d, J=6Hz)

Example 9 Preparation of sodium7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]-3-(3-amino-1-5pyridinio)methyl 3-cephem-4-carboxylate (syn-isomer)

The same operations as in steps of (A), (B) and (C) of Example 7 wereconducted by using 773 mg (0.75 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]3-iodomethyl-3-cephem-4-carboxylate1-oxide (syn-isomer) and 276.5 mg (0.83 mmol) of 3-tritylaminopyridine.The trifluoroacetate obtained in step of (C) was adjusted to pH 6.5 witha sodium bicarbonate aqueous solution, then subjected to ODS columnchromatography and eluted with a 5% methanol aqueous solution to obtain23 mg (yield: 5.4%) of the above-identified compound.

mp: 125° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 1770, 1620, 1540, 1400, 1200

NMR(DMSO-d₆ /D₂ O)δ: 3.20-3.60(2H, ABq), 5.00-5.25(5H, m), 5.65(1H, d,J=4.5Hz), 6.90(1H, s), 7.60-8.40 (4H, m)

Example 10 Preparation of sodium7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]-3-(3-formylamino-1-pyridinio)methyl-3-cephem-4-carboxylate(syn-isomer)

The same operation as in Example 9 was conducted by using 773 mg (0.75mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate1-oxide (syn-isomer) and 101 mg (0.83 mmol) of 3-formylaminopyridine.The product was subjected to ODS column chromatography and eluted with a5% methanol aqueous solution to obtain 125 mg (yield: 27.9%) of theabove-identified compound.

mp: 120° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 1770, 1660, 1600, 1540, 1500, 1400

NMR(DMSO-d₆ /D₂ O)δ: 3.20-3.60(2H, ABq), 4.95-5.20(4H, m), 5.05(1H, d,J=4.5Hz), 5.70(1H, d, J=4.5Hz), 6.85 (1H, s), 7.60-8.40(4H, m), 9.45(1H,s)

Example 11 Preparation of disodium7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thiomethyl-3-cephem-4-carboxylate(syn-isomer)

(A) 461 mg (0.5 mmol) of benzhydryl3-chloromethyl-7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiano-4-yl)acetamido]-3-cephem-4-carboxylate(syn-isomer) was dissolved in 8 ml of N,N-dimethylforamide, and 375 mg(2.35 mmol) of sodium iodide was added thereto. The mixture was stirredat room temperature for 50 minutes. To the reaction solution, 105 mg(0.5 mmol) of 5-(3,4-dihydroxyphenyl)-2-mercapto-1,3,4-oxadiazole wasadded, and the mixture was stirred for 1 hour. To the reaction solution,50 ml of ethyl acetate was added, and the mixture was washed with waterand then dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure. To the residue, diethyl ether was added toobtain 420 mg of crude benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazol-2-yl]thiomethyl-3-cephem-4-carboxylate.The crude product was used for the subsequent reaction withoutpurification.

(B) 440 mg (0.36 mmol) of the compound obtained in the above reaction(A) was dissolved in 5 ml of methylene chloride and 1 ml of anisole, andthe solution was cooled to 0° C. A solution of 5 ml of methylenechloride and 10 ml of trifluoroacetic acid which was previously cooledto 0° C., was added thereto all at once. The mixture was stirred for 1hour. The solvent was distilled off under reduced pressure. To theresidue, diethyl ether was added, and the precipitates were collected byfiltration. The precipitates were suspended in water. The suspension wasadjusted to 1H-7.1 with a saturated sodium bicarbonate aqueous solutionand then subjected to reversed phase column chromatography (LC-SorbRP-18, manufactured by Kemco Co.) and eluted with a 8% methanol aqueoussolution. The eluted fraction containing the desired compound wasconcentrated and freeze-dried to obtain 114 mg (yield: 44%) of theabove-identified compoud.

mp: 190° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 1760, 1600, 1400

NMR(D₂ O)δ: 3.45 and 3.78(2H, ABq, J=17.5Hz), 4.17(2H, br s), 5.17(1H,d, J=4.5Hz), 5.22(1Hd, J=2Hz), 5.36(1H, d, J=2Hz), 5.82(1H, d, J=4.5Hz),6.84(1H, br s), 7.10-7.20(3H, m)

Example 12 Preparation of disodium7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]-3-[4-(3,4-dihydroxyphenyl)thiazol-2-yl]thiomethyl-3-cephem-4-carboxylate(syn-isomer)

(A) The same operation as in step (A) of Example 11 was conducted byusing 1.17 g (1.12 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-4-carboxylate(syn-isomer) and 0.3 g (1.33 mmol) of4-(3,4-dihydroxyphenyl)-2-mercaptothiazole to obtain 0.96 g (yield:74.9%) of benzhydry17β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]3-[4-(3,4-dihydroxyphenyl]thiazol-2-yl]thiomethyl-3-cephem-4-carboxylate(syn-isomer).

NMR(DMSO-d₆ /D₂ O)δ: 1.42(9H, s), 37.0(2H, m), 4.20(1H, d, J=14Hz),4.46(1H, d, J=14Hz), 5.15(1H, br s), 5.18 (1H, d, J=5Hz), 5.32(1H, brs), 5.72(1H, m), 6.73 (1H, s), 6.85(1H, s), 6.94(1H, s), 7.00-7.70(27H,m)

(B) 0.96 g (0.84 mmol) of the compound obtained in the above reaction(A) was subjected to the same operation as in step (B) of Example 11 toobtain 225 mg (yield: 41.4%) of the above-identified compound.

mp: 110° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 1742, 1517

NMR(DMSO-d₆)δ: 3.53(2H, m), 4.48(2H, m), 4.88(1H, br s), 5.01(1H, d,J=4Hz), 5.18(1H, br s), 5.65(1H, m), 6.78(1H, d, J=9Hz), 6.90(1H, s),7.18(1H, dd, J=2 and 9Hz), 7.76(1H, d, J=2Hz), 7.56(1H, s)

Example 13 Preparation of disodium7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylate(syn-isomer)

(A) The same operation as in step (A) of Example 11 was conducted byusing 1.0 g (0.96 mmol) of benzhydryl7β-[2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (syn-isomer) and0.24 g (1.06 mol) of5-(3,4-dihydroxyphenyl)-2-mercapto-1,3,4-thiadiazole to obtain 425 mg(yield: 41%) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylate(syn-isomer) as foamy substance.

NMR(DMSO-d₆)δ: 1.47(9H, s), 3.70(2H, m), 4.20(1H, br d, J-12Hz),4.52(1H, br d, J=12Hz), 5.20(1H, br s), 5.22 (1H, d, J=5Hz), 5.35(1H, brs), 5.75(1H, m), 6.88 (1H, m), 6.90(1H, s), 7.00-7.70(27H, m), 8.88(1H,m), 9.78(1H, m)

(B) 451 mg (0.39 mmol) of the compound obtained in the above reaction(A) was subjected to the same operation as in step (B) of Example 11 toobtain 68 mg (yield: 24%) of the above-identified compound.

mp: 160° C. (decomposed)

IR(KBr)cm⁻¹ : 3430, 1765, 1600, 1540

NMR(DMSO-d₆ /D₂ O) δ: 3.53(2H, m), 4.50(2H, m), 4.92(1H, br s), 5.05(1H,d, J=4Hz), 5.22(1H, br s), 5.66(1H, m), 6.90 (1H, m), 6.92(1H, s),7.15(1H, m), 7.30(1H, br s)

Example 14 Preparation of disodium7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]-3-[5-(3,4-dihydroxyphenyl)oxazol-2-yl]thiomethyl-3-cephem-4-carboxylate(syn-isomer)

(A) The same operation as in step (A) of Example 11 was conducted byusing 1.0 g (1.06 mmol) of benzhydryl7β-[2-(1-tert=butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn-isomer), 175 mg (1.17 mmol) of sodium iodide and 0.260 g (1.21mmol) of 5-(3,4-dihydroxyphenyl)-2-mercaptooxazole to obtain 0.75 g(yield: 63.2%) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyl-oxy-imino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[5-(3,4-dihydroxyphenyl)oxazol-2-yl]thiomethyl-3-cephem-4-carboxylate(syn-isomer).

IR(KMr)cm⁻¹ : 1790, 1720, 1660, 1530, 1370, 1150, 700

NMR(DMSO-d₆)δ: 1.40(9H, s), 3.55-3.80(2H, m), 3.90-4.35 (2H, m),5.10-5.35(3H, m), 5.70(1H, m), 6.70-7.70 (31H, m), 9.25(1H, m)

(B) 0.72 g (0.64 mmol) of the compound obtained in the above reaction(A) was subjected to the same operation as in step (B) of Example 11.The trifluoroacetate thereby obtained was suspended in water. Thesuspension was adjusted to pH 6.5 with a saturated sodium bicarbonateaqueous solution, and then the insolubles were removed by filtration.The filtrate was subjected to reversed phase column chromatography(LC-Sorb RP-18, manufactured by Kemco Co.). The eluted fractionscontaining the desired compound (eluted with a 3% methanol aqueoussolution), were gathered, concentrated and freeze-dried to obtain 110

mg (yield: 27.2%) of the above-identified

mp: 190° C. (decomposed)

IR(KBr)cm-⁻¹ : 1760, 1600, 1530, 1400, 1280, 1200, 1010

NMR(DMSO-d₆ /D₂ O)δ: 3.30-3.70(2H, m), 4.30(2H, br s), 4.80-5.25((3H,m), 5.63(1H, m), 6.75-7.15(4H, m), 7.33(1H, s)

Example 15 Preparation of trisodium78-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]-3-[4-carboxylato-5-(3,4-dihydroxyphenyl)thiazol-2-yl]thiomethyl-3-cephem-4-carboxylate(syn-isomer)

(A) 11.43 g (12 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn-isomer) was dissolved in 90 ml of N,N-dimethylformamide, and 8.3 g(55 mmol) of sodium iodide was added thereto. The mixture was stirred atroom temperature for 1 hour. To the reaction solution, 3.23 g (12 mmol)of 4-carboxy-5-(3,4-dihydroxyphenyl)-2-mercaptothiazole and 1.67 ml (12mmol) of triethylamine were added, and the mixture was stirred at thesame temperature for 45 minutes. The solvent was distilled off underreduced pressure. To the residue, 500 ml of ethyl acetate and 150 ml ofwater were added, and the mixture was adjusted to pH 1.5 with 2Nhydrochloric acid. The organic layer was washed with 150 ml of a 5%sodium thiosulfate aqueous solution and with 150 ml of a saturatedsodium chloride aqueous solution, then dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue wassubjected to silica gel column chromatrography (Wakogel C-300, elutedwith 2% methanol/chloroform) to obtain 8.33 g (yield: 59%) of benzhydryl7β-[2-(1-benzhydryloxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[4-carboxy-5-(3,4-dihydroxyphenyl)thiazol-2-yl]thiomethyl-3-cephem-4-carboxylate(syn-isomer).

IR(KBr)cm⁻¹ : 1790, 1720, 1680, 1640, 1530, 1500, 1370, 1280, 1200, 1150

NMR(DMSO-d₆)δ: 1.46(9H, s), 3.75(2H, ABq), 4.27 (2H, ABq), 5.19((1H, s),5.22(1H, d, J=4.5Hz), 5.35 (1H, s), 5.75(1H, dd, J=4.5 and 9Hz),6.77(2H, s), 6.93(2H, s), 6.96(1H, s), 7.35(25H, s), 8.86 (1H, br s),9.16(1H, br s), 9.33(1H, br s), 9.77(1H, d, J=9Hz)

(B) 8.30 g of the compound obtained by the above reaction

(A) was dissolved in 38 ml of methylene chloride and 7.6 ml of anisole,and 38 ml of trifluoroacetic acid was dropwise added thereto over aperiod of 20 minutes at -10° C. The mixture was stirred at roomtemperature for 2 hours. The reaction solution was concentrated underreduced pressure, and 200 ml of diisopropyl ether was added to the oilyresidue. The precipitated insolubles were collected by filtration. Theprecipitated insolubles were washed with diisopropyl ether (50 ml×2times) and dried under reduced pressure to obtain 5.53 g (yield: 85%) ofthe trifluoroacetate of the above-identified compound as powder.

NMR(DMSO-d₆)δ: 3.73(2H, ABq), 4.35(2H, Aβq), 5.19(1H, d,J=4.5Hz),5.41(1H, s), 5.48(1H, s), 5.83(1H, dd, 6.91(1H, s), 7.03(1H,s), 9.83(1H, d, J=9Hz)

(C) 5.45 g (7.26 mmol) of the compound obtained in the above reaction(B) was suspended in 80 ml of water, and the suspension was adjusted topH 7.3 with a saturated sodium bicarbonate aqueous solution undercooling with ice. The insolubles were removed by filtration. Thefiltrate was subjected to reversed phase column chromatography (LC-SorbRP-18, manufactured by Kemco Co., eluted with water). The elutedfraction containing the desired compound was concentrated andfreeze-dried to obtain 2.51 g (yield: 44%) of the above-identifiedcompound.

mp: 270° C. (decomposed)

IR(KBr)cm⁻¹ : 1760, 1670, 1595, 1540, 1405

NMR(D20)6 3.57(2H, ABq), 4.18(2H, ABq), 5.17(1H, d, J=4.5Hz), 5.19(1H,s), 5.34(1H, s), 5.80(1H, d, J=4.5Hz), 6.88(2H, s), 6.98(1H, s),7.17(1H, s)

Example 16 Preparation of trisodium3-[4-(3,4-diacetoxyphenyl)-5-carboxylatomethylthiazol-2-yl]thiomethyl-7.beta.-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]-3-cephem-4-carboxylate (syn-isomer)

(A) 5.0 g (9.01 mmol) of2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid (syn-isomer) and 3.73 g (9.0 mmol) of benzhydryl7β-amino-3-chloromethyl-3-cephem-4-carboxylate were dissolved in 80 mlof methylene chloride, and 5.11 ml (40.5 mmol) of N,N-dimethylanilineand then 1.01 ml (10.8 mmol) of phosphorus oxychloride were dropwiseadded thereto under cooling with ice. The mixture was stirred at roomtemperature for 1 hour. Then, the reaction solution was washedsequentially with 0.5N hydrochloric acid and with a saturated sodiumchloride aqueous solution and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain the foamyresidue of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn-isomer). The product was used for the subsequent reaction withoutpurification.

(B) The compound obtained in the above reaction

(A) was dissolved of 200 ml of acetone, and 2.7 g (18 mmol) of sodiumiodide was added thereto. The mixture was stirred at room temperaturefor 30 minutes. The solvent was distilled off under reduced pressure,and to the residue, ethyl acetate was added. The mixture was washed withwater and with a saturated sodium chloride aqueous solution and driedover anhydrous sodium sulfate. The solvent was distilled off to obtain10.2 g of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate(syn-isomer).

NMR(DMSO-d₆)δ: 1.48(9H, s), 3.30-3.90(2H, m), 4.35 (2H, m), 5.18(1H, brs), 5.22(1H, d, J=5.0Hz), 5.36(1H, br s), 5.75(1H, m), 6.90-7.80(27H,m), 8.88 (1H, br s), 9.80(1H, br d, J=8.0Hz)

(C) 1.13 g (about 1.08 mmol) of the crude product obtained in the abovereaction

(B) was dissolved in 10 ml of N,N-dimethylformamide, and 0.58 g (1.09mmol) of4-(3,4-diacetoxyphenyl)-5-benzhydryloxycarbonylmethyl-2-mercaptothiazolewas added thereto. The mixture was stirred at room tmeperature for 1hour. The solvent was distilled off under reduced pressure to obtainbenzhydryl3-[4-(3,4-diacetoxyphenyl)-5-benzhydryloxycarbonylmethylthiazol-2-yl]thiomethyl-7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate(syn-isomer). The product was used for the subsequent reaction withoutpurification.

(D) The crude product obtained in the above reaction

(C) was dissolved in 5.0 ml of methylene chloride and 1.0 ml of anisole,and 5.0 ml of trifluoroacetic acid was added thereto under cooling withice. The mixture was stirred for 1 hour. The solvent was distilled offunder reduced pressure, and to the residue, diethyl ether was added. Theprecipitates were collected by filtration and suspended in water. Thesuspension was adjusted to pH 6.5 with a saturated sodium bicarbonateaqueous solution, then subjected to reversed phase column chromatography(LC-Sorb RP-18, manufactured by Kemco Co.) and eluted with a 5% methanolaqueous solution. The eluted fractions containing the desired compondwere gathered, concentrated and freeze-dried to obtain 122 mg (yieldbased on step (B): 13%).

mp: 180°-185° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 1760, 1590, 1535, 1370, 1210

NMR(DMSO-d₆)δ: 2.30(6H, s), 4.10-4.80(2H, m), 4.95(1H, br s),5.03(1H, d,J=5.0Hz), 5.22(1H, br s), 5.62(1H, m), 6.95(1H, s), 7.20-7.70(3H, m)

Example 17 Preparation of disodium7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]cephalosporanate(syn-isomer)

(A) To a mixed solution of 0.18 ml (1.93 mmol) of phosphorus oxychlorideand 0.544 ml of ethyl acetate, 0.15 ml (1.93 mmol) ofN,N-dimethylformamide was added, and the mixture was stirred at roomtemperature for 30 minutes. Then, the reaction solution was cooled to 0°C., and 2 ml of ethyl acetate and 841 mg (1.51 mmol) of2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)-aceticacid (syn-isomer) were added thereto. The mixture was stirred for 1hour.

A suspension of 546 mg (2 mmol) of 7β-aminocephalosporanio acid in 8 mlof acetone and 12 ml of water, was adjusted to pH 7.5 with a 2N sodiumhydroxide aqueous solution and then dropwise added to the solutioncontaining the reactive derivative of the carboxylic acid as previouslyprepared over a period of 20 minutes while keeping the solution at pH7.5 to 8.5. Further, the mixture was stirred for 1 hour. To the reactionsolution, 50 ml of ethyl acetate was added, and the mixture was adjustedto pH 2.0 with 4N hydrochloric acid. The insolubles were removed byfiltration. The organic layer was washed with a saturated sodiumchloride aqueous solution and then dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the residuewas subjected to silica gel column chromatography (Wakogel C-300, elutedwith 0 to 4% methanol/chloroform). The eluted fraction containing thedesired compound was concentrated to obtain 600 mg (yield: 49.1%) of7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanicacid (syn-isomer).

IR(KBr)cm⁻¹ : 3400, 2960, 1790, 1720, 1530, 1220, 1150

NMR(DMSO-d₆)δ: 1.45(9H, s), 2.00(3H, s), 2.60-2.90 (2H, m), 4.63 and4.96(2H, ABq, J=13Hz), 5.06(1H, d, J=5Hz), 5.13(1H, s), 5.30(1H, s),5.65(1H, dd, J=5 and 7.5Hz), 6.88(1H, s), 7.30(15H, s), 8.83(1H, br s),9.70(1H, d, J=7.5Hz)

(B) 560 mg (0.69 mmol) of the compound obtained in the above reaction(was dissolved in 3 ml of methylene chloride and 0.6 ml of anisole, andthe solution was cooled with ice. Then, to the solution, a mixedsolution of 6 ml of trifluoroacetic acid and 3 ml of methylene chloridewhich was previously cooled to 0° C. was added all at once, and themixture was stirred at the same temperature for 30 minutes and at roomtemperature for 1 hour. The solvent was distilled off under reducedpressure, and to the residue, diisopropyl ether was added to obtainpowder. The powder was suspended in 5 ml of water, and the suspensionwas adjusted to pH 6.5 with a 1N sodium hydrogencarbonate aqueoussolution. The insolubles were removed by filtration. Then, the filtratewas subjected to reversed phase column chromatography (LC-Sorb RP-18,manufactured by Kemco Co., eluted with water). The eluted fractioncontaining the desired compound was concentrated and freeze-dried toobtain 228 mg (yield: 59.5%) of the above-identified compound.

mp: 150°-155° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 1770, 1600, 1520, 1400

NMR(DMSO-d₆ /TFA)δ: 2.05(3H, s), 3.36 and 3.65(2H, ABq, J=18Hz), 4.67and 5.00(2H, ABq, J=15Hz), 5.15(1H, d, J=5Hz), 5.33(1H, s), 5.43(1H, s),5.80(1H, dd, J=5 and 8Hz), 6.99(1H, s), 9.75(1H, d, J=8Hz)

Example 18 Preparation of disodium7β-[2-(2-aminothiazol-4-yl)-2-11-carboxylato-1-vinyloxyimino)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(syn-isomer)

(A) The same operation as in step

(A) of Example 17 was conducted by using 841 mg (1.51 mmol) of2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid (syn-isomer) and 625 mg (2 mmol) of7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid to obtain 480 mg (yield: 37.4%) of7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn-isomer).

IR(KBr)cm⁻¹ : 3400, 2960, 1790, 1720, 1690, 1530, 1370,

NMR(DMSO-d₆)δ: 1.45(9H, s), 2.66(3H, s), 3.75(2H, ABq, J=18Hz), 4.19 and4.51(2H, ABq, J=15Hz), 5.10(1H, d, J=5Hz), 5.13(1H, s), 5.31(1H, s),5.63(1H, dd, J=5 and 8Hz), 6.90(1H, s), 7.30(15H, br s), 8.80(1H, br s),9.70(1H, d, J=8Hz)

(B) 440 mg (0.52 mmol) of the compound obtained in the above reaction(A) was subjected to the same operation as in step (B) of Example 17 toobtain 185 mg (yield: 57.0%) of the above-identified compound.

mp: 157°-160° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 1760, 1600, 1400, 1210

NMR(D₂ O)δ: 2.72(3H, s), 3.38 and 3.80(2H, ABq, J=17Hz), 3.96(2H, ABq),5.18(2H, d, J=5Hz), 5.20(1H, s), 5.35 (1H, s), 5.82(1H, d, J=5Hz),7.16(1H, s)

Example 19 Preparation of disodium7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(syn-isomer)

(A) The same operation as in step

(A) of Example 17 was conducted by using 841 mg (1.51 mmol) of2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid (syn-isomer) and 657 mg (2 mmol) of7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-carboxylicacid to obtain 670 mg (yield: 51.2%) of7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn-isomer).

IR(KBr)cm⁻¹ : 3400, 2970, 1790, 1720, 1680, 1530, 1370, 1150

NMR(DMSO-d₆)δ: 1.45(9H, s), 3.50 and 3.72(2H, ABq, J=15Hz), 3.90(3H, s),4.14 and 4.36(2H, ABq, J=15Hz), 5.06(1H, d, J=5Hz), 5.10(1H, s),5.29(1H, s), 5.52 (1H, dd, J=5 and 8Hz), 6.87(1H, s), 7.30(15H, s),8.80(1H, br s), 9.76(1H, d, J=8Hz)

(B) The same operation as in step

(B) of Example 17 was conducted by using 630 mg (0.73 mmol) of thecompound obtained in the above reaction

(A) to obtain 195.5 mg (yield: 43.9%) of the above-identified compound.

mp: 155°-160° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 1765, 1600, 1540, 1400, 1210

NMR(D₂ O)δ: 3.43 and 3.82(2H, ABq, J=19Hz), 4.06(3H, s), 4.20(2H, ABq),5.20(1H, d, J=5Hz), 5.22(1H, s), 5.37 (1H, s), 5.83(1H, d, J=5Hz),7.18(1H, s)

Example 20 Preparation of trisodium7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxylato-1-vinyloxyimino)acetamido]-3-(1-carboxylatomethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(syn-isomer)

(A) The same operation as in step

(A) of Example 17 was conducted by using 841 mg (1.51 mmol) of2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid (syn-isomer) and 745 mg (2 mmol) of7β-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid to obtain 300 mg (yield: 21.9%) of7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylicacid (syn-isomer).

IR(KBr)cm⁻¹ : 3400, 2970, 1785, 1720, 1640, 1590, 1570, 1150, 1040

NMR(DMSO-d₆)δ: 1.45(9H, s), 3.60(2H, br), 4.13 and 4.43 (2H, ABq,J=15Hz), 5.05(1H, d, J=5Hz), 5.20(2H, s), 5.25(2H, s), 5.30(1H, s),5.43(1H, s), 5.60(1H, dd, J=5 and 8Hz), 6.95(1H, s), 7.40(15H, s), 9.46(1H, br s), 9.75(1H, d, J=8Hz)

(B) The same operation as in step

(B) of Example 17 was conducted by using 260 mg (0.29 mmol) of thecompound obtained in the above reaction

(A) to obtain 97.1 mg (yiled: 50.2%) of the above-identified compound.

mp: 157°-162° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 1760, 1620, 1540, 1400, 1210

NMR(D₂ O)δ: 3.43 and 3.80(2H, ABq, J=17Hz), 4.08 (2H, ABq), 5.05(2H, s),5.19(1H, d, J=5Hz), 5.21(1H, s), 5.33(1H, s), 5.83(1H, d, J=5Hz), 7.20(1H, s)

Example 21 Preparation of7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylicacid trifluoroacetate (syn-isomer)

210 mg (0.23 mmol) of benzhydryl7β-[2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn-isomer) obtained in step

(A) of Example 1, was dissolved in 5 ml of methylene chloride and 1 mlof anisole. 5 ml of trifluoroacetic acid was added thereto under coolingwith ice. The mixture was stirred for 1.5 hours. The solvent wasdistilled off under reduced pressure, and to the residue, 20 ml ofisopropyl ether was added. The precipitated powder was collected byfiltration and dried to obtain 115 mg (yield: 83.8%) of theabove-identified compound.

mp: 130° C. (decomposed)

IR(KBr)cm⁻¹ : 340, 780, 1660, 1630, 1190, 1000

NMR(DMSO-d₆)δ: 3.60(2H, br s), 4.55(2H, br s), 5.18 (1H, d, J=5Hz),5.46(2H, br s), 5.80(1H, dd, J=5 and 9Hz), 7.02(1H, s), 9.82(1H, d,J=9Hz)

Example 22 Preparation of2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid (syn-isomer)

6.03 g (20.8 mmol) of N-(1-tert-butoxycarbonyl-1-vinyloxy)phthalimideprepared in accordance with the method disclosed in British Patent No.1,602,725, was dissolved in a mixed solution of 200 ml of methylenechloride and 10 ml of methanol. Then, a solution of 1.88 ml of 80%hydrazine hydrate in 40 ml of methanol was dropwise added thereto. Themixture was stirred at room temperature for 1.5 hours. The insolubleswere removed, and then the filtrate was washed three times with 8%aqueous ammonia and with a saturated sodium chloride aqueous solutionand dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure to obtain a residue of0-(1-tert-butoxycarbonyl-1-vinyl)hydroxylamine. The residue wasdissolved in 120 ml of methanol, and 7.46 g (18 mmol) of2-(2-tritylaminothiazol-4-yl)glyoxylic acid was added thereto, and themixture was stirred at room temperature for three hours. Theprecipitated crystals were collected by filtration to obtain 7.08 g(yield: 70.9%) of the above-identified compound.

mp: 110°-115° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 2970, 1725, 1630, 1100, 700

NMR(DMSO-d δ: 1.45(9H, s), 5.20(1H, br s), 5.33 (1H, br s), 7.05(1H, s),7.10-7.40(15H, m), 8.82 (1H, br s)

Elemental analysis value: as C₁₃ H₂₉ N₃ O₆ S Calculated value (%): C67.00; H 5.26; N 7.56; S 5.77. Formed value (%): C 67.00; H 5.58; N6.74; S 5.54.

Example 23 Preparation of2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid (syn-isomer)

392 mg (1.3 mmol) of N-(1-tert-butoxycarbonyl-1-vinyloxy)phthalimide wasdissolved in a mixed solution of ml of methylene chloride and 0.8 ml ofmethanol, and then a solution of 0.165 ml (2.6 mmol) of 80% hydrazinehydrate and 2 ml of methanol was dropwise added thereto. The mixture wasstirred at room temperature for 1 hour. The insolubles were removed, andthen the filtrate was washed three times with 8% aqueous ammonia andwith a saturated sodium chloride aqueous solution and dired overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain a residue ofO-(1-tert-butoxycarbonyl-1-vinyl)hydroxylamine. The residue wasdissolved in 5 ml of methanol, and then 414 mg (1.0 mmol) of2-(2-tritylaminothiazol-4-yl)glyoxylic acid was added thereto. Themixture was stirred at room temperature for 2 hours. The precipitatedcrystals were collected by filtration to obtain 400 mg (yield: 76.1%) ofthe above-identified compound. The IR and NMR spectra of the productcompletely agreed with those of the product of Example 22.

Example 24 Preparation of2-(2-aminothiazol-4-yl)-2-(1-tert-butoxvcarbonyl-1-vinyloxyimino)aceticacid (syn-isomer)

The same operation as in Example 22 was conducted by using 172 mg (1.0mmol) of 2-(2-aminothiazol-4-yl)glyoxylic acid to obtain 207.5 mg(yield: 66.2%) of the above-identifed compound.

mp: 120° C. (decomposed)

IR(KBr)cm⁻¹ :3400, 3150, 2990, 1720, 1640, 1380, 1320, 1200, 1150, 980,850, 730

NMR(DMSO-d₆ /CO₃ OD)δ: 1.48(9H, s), 5.29(1H, s), 5.39 (1H, s), 7.10(1H,s), 7.30(2H, br s)

Example 25 Preparation of2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-formamidethiazol-4-yl)aceticacid (syn-isomer)

The same operation as in Example 22 was conducted by using 200 mg (1.0mmol) of 2-(2-formamidothiazol-4-yl)glyoxylic acid to obtain 183 mg(yield: 53.6%) of the above identified compound.

mp: 130° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 3150, 2980, 1720, 1690, 1630, 1560, 1400, 1380,1280, 1210, 1150, 980, 850, 740

NMR(DMSO-d₆)δ: 1.48(9H, s), 5.18(1H, s), 5.24(1H, s), 7.49(1H, s),8.51(1H, s)

Example 26 Preparation of2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetic acidtrifluoroacetate (syn-isomer)

350 mg (0.63 mmol) of2-(1-tert-butoxycarbonyl-1-vinyloxyimino)-2-(2-tritylaminothiazol-4-yl)aceticacid (syn-isomer) was dissolved in a mixed solution of 4 ml of methylenechloride and 0.8 ml of anisole, and the solution was cooled to 0° C.Then 4 ml of trifluoroacetic acid as previously cooled to 0° C., wasadded thereto, and the mixture was stirred at the same temperature for30 minutes and at room temperature for 1.5 hours. The solvent wasdistilled off under reduced pressure, and to the oily residue, 20 ml ofdiisopropyl ether was added. The precipitated powder was collected byfiltration and washed with diisopropyl ether to obtain 200 mg (yield:85.5%) of the above-identified compound.

mp: 110°-115° C. (decomposed)

IR(KBr)cm⁻¹ : 3400, 3120, 1650, 1630, 1610, 1590, 1190, 1180, 980

NMR(DMSO-d₆ /D₂ O)δ: 5.40(1H, s), 5.47(1H, s), 7.15 (1H, s)

REFERENCE EXAMPLES Reference Example 1 Preparation ofO-(1-tert-butoxycarbonyl-1-vinyl)hydroxylamine

602 mg (2.0 mmol) of N-(1-tert-butoxycarbonyl-1-vinyloxy)phthalimideprepared in accordance with the method disclosed in British Patent No.1,602,725, was dissolved in a mixed solution of 5 ml of methylenechloride and 0.5 ml of methanol. Thn, a solution of 0.25 ml (5 mmol) ofhydrazine hydrate and 0.5 ml of methanol was dropwise added theretounder cooling with ice, and the mixture was stirred at room temperaturefor 1.5 hours. The solvent was distilled off under reduced pressure, andto the residue, 20 ml of ethyl acetate was added. The mixture was washedtwice with 8% aqueous ammonia and twice with a saturated sodium chlorideaqueous solution and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure to obtain 260 mg (yield: 78.5%)of the above-identified 844compound.

IR(KBr)cm⁻¹ : 3300, 2970, 1720, 1640, 1370, 1330, 1220, 1150

NMR(DMSO-d₆)δ: 1.50(9H, s), 5.18(1H, s), 5.25(1H, s), 6.10(2H, br s)

Reference Example 2 Preparation of2-mercapto-5-[3,4-di(2-methoxyethoxymethoxy)phenyl]-1,3,4-oxadiazole

(A) 2.5 g (14.9 mmol) of methyl protocatechuate was suspended in 50 mlof methylene chloride, and 7.84 ml (45 mmol) of N-ethyldiisopropylaminewas added therero at 0° C. to obtain a homogeneous solution. 5.8 ml (45mmol) of 2-methoxyethoxymethyl chloride was dropwise added thereto, andthe mixture was stirred for 30 minutes. Then, the reaction solution waswashed sequentially with water, with a 0.5N sodium hydroxide aqueoussolution and with a saturated sodium chloride aqueous solution. Further,the aqueous layer was extracted twice with methylene chloride. Theextract and the organic layer were put together and dried over anhydroussodium sulfate. Then, the solvent was distilled off under reducedpressure to obtain 5.1 g (yield: 99%) of methyl3,4-di(2-methoxyethoxymethoxy)benzoate.

NMR(CDCl₃)δ: 3.32(3H, s), 3.34(3H, s), 3.55(4H, m), 3.83(4H, m),3.86(3H, s), 5.32(4H, m), 7.18(1H, d, J=9Hz), 7.67(1H, dd, J=2 and 9Hz),7.79(1H, d, J=2Hz)

(B) 5.1 g (15 mmol) of the compound obtained in the above reaction

(A) was dissolved in 100 ml of methanol, and 40 ml (300 mmol) of 80%hydrazine hydrate was added thereto. The mixture was refluxed underheating for 1 hour. Then, 40 ml of 80% hydrazine hydrate was furtheradded thereto, and the mixture was again refluxed under heating for 2hours. The reaction solution was cooled, then poured into water andextracted twice with ethyl acetate. The extract was washed with asaturated sodium chloride aqueous solution and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain 4.2 g of crude 3,4-di(2-methoxyethoxymethoxy)benzohydrazide. (C)To 42 ml of an ethanol solution containing 1.27 g of 80% potassiumhydroxide (18 mmol; 1.0 g of potassium hydroxide and.0.17ml of water),4.2 g (12 mmol) of the compound obtained in the above reaction

(B) and 3.64 ml (61 mmol) of carbon disulfide were added, and themixture was refluxed under heating for 1 hour. The solvent was distilledoff under reduced pressure. Then, the residue was dissolved in water,and the solution was adjusted to pH 1.5 with 1N hydrochloric acid andextracted three times with ethyl acetate. The organic layer was washedwith a saturated sodium chloride aqueous solution and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was subjected to silica gel columnchroamtography (Wakogel C-300, ethyl acetate/hexane=3/1) to obtain 3.03g (yield: 52.3%) of the above-identified compound.

MP: 84° C.

IR(KBr)cm⁻¹ :1620, 1585, 1520, 1500, 1360, 1250, 1105, 1090, 995

NMR(DMSO-d₆)δ: 3.27(6H, s), 3.51(4H, m), 3.80(4H, m), 5.38(2H, s),5.39(2H, s), 7.32(1H, d, J=6Hz), 7.54 (1H, dd, J=1.8 and 6Hz), 7.62(1H,d, J=1.8Hz)

Elemental analysis value: as C₁₆ H₂₂ N₂ O₇ S Calculated value (%): C49.73; H 5.74; N 7.25; S 8.30. Found value (%): C 49.66; H 5.85; N 7.10;S 8.24.

Reference Example 3 Preparation of2-mercapto-5-[3,4-di(2-methoxyethoxymethoxy)phenyl]-1,3,4-thiadiazole

(A) 15.0 g (50.7 mmol) of 3,4-di(2-methoxyethoxymethoxy)benzonitrile wasdissolved in 15.0 ml of pyridine, and 7.5 ml (50 mmol) of triethylaminewas added thereto. To this solution, hydrogen sulfide gas was introducedand stirred at room temperature for 6 hours. To the reaction solution,ethyl acetate and water were added. The organic layer was separated andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure to obtain 18.8 g (yield: 100%) of crude3,4-di(2-methoxyethoxymethoxy)thiobenzamide. The product was used forthe subsequent reaction without purification.

IR(KBr)cm⁻¹ : 3320, 3200, 2900, 1635, 1515

(B) 2.0 g (5.8 mmol) of the compound obtained in the above reaction (A)was dissolved in 20.0 ml of ethanol, and 0.40 ml of hydrazine hydratewas added thereto. The mixture was stirred at 70° C. for 1 hour. To thereaction solution, 0.40 g (5.70 mmol) of potassium hydroxide and 1.38 ml(18 mmol) of carbon disulfide were added, and the mixture was refluxedfor 20 minutes. The solvent was distilled off under reduced pressure.The residue was dissolved in water and washed with ethyl acetate. Theaqueous layer was adjusted to pH 3.0 with 2N hydrochloric acid, thenextracted with ethyl acetate and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the crystalresidue was washed with diethyl ether to obtain 0.94 g (yield: 40%) ofthe above-identified compound.

IR(KBr)cm⁻¹ : 3160, 2500, 1600, 1585, 1510, 1455

NMR(DMSO-d₆)δ: 3.25(6H, s), 3.50(4H, m), 3.78(4H, m), 5.34(4H, br s),7.26(1H, d, J=8Hz) 7.33(1H, dd, J=1 and 8Hz), 7.52(1H, d, J=1Hz)

Elemental analysis value (%): as C₁₆ H₂₂ N₂ O₆ S₂ Calculated value: C47.75; H 5.51; N 6.96; S 15.93. Found value: C 47.75; H 5.44; N 6.94; S15.72.

Reference Example 4 Preparation of5-(3,4-dihydroxyphenyl)-2-mercapto-1,3,4-thiadiazole

(A) 10 g (178 mmol) of potassium hydroxide was dissolved in 400 ml ofethanol, and 20 g (119 mmol) of protocatechuhydrazide was added theretounder stirring at a temperature of at most 5° C. To this solution, 28.0ml of carbon disulfide was dropwise added over a period of 10 minutes ata temperature of at most 10° C., and the mixture was stirred at atemperature of from 0 to 10° C. for 30 minutes. Then, the precipitateswere collected by filtration, washed with ethanol and dried to obtain25.3 g (yield: 75.3%) of potassium 3-protocatechuoyldithiocarbazate.

(B) 25.3 g (89.6 mmol) of the compound obtained in the above reaction

(A) was gradually added to 125 ml of concentrated sulfuric acid over aperiod of 20 minutes at a temperature of at most 10° C. Then, themixture was stirred at 10° C. for 20 minutes. The reaction solution wasgradually added to 600 g of ice and 300 ml of water, and then themixture was further stirred for 10 minutes. The precipitates werecollected by filtration and dissolved in 125 ml of acetone. 600 ml ofethyl acetate, 20 ml of water and 1 g of activated carbon were addedthereto, and the mixture was stirred for 15 minutes. The activatedcarbon was removed by filtration, and then the filtrate was washedsequentially with 200 ml of a 5% sodium thiosulfate aqueous solution,with 150 ml of water and with a saturated sodium chloride aqueoussolution. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was distilled off. The crystal residue was washed withdiethyl ether to obtain 3.6 g (yield: 17.8%) of the above-identifiedcompound.

IR(KBr)cm⁻¹ : 3600-2000, 1650, 1600, 1430, 1300, 1250

NMR(DMSO-d₆)δ: 6.82(1H, d, J=9Hz), 7.01(1H, dd, J=2 and 9Hz), 7.13(1H,d, J=2Hz), 9.50(2H, br s), 14.38(1H, br s)

Reference Example 5 Preparation of4-(3,4-dihydroxyphenyl)-2-mercaptothiazole

10.0 g (53.6 mmol) of 2-chloro-3'4'-dihydroxy-acetophenone was dissolvedin 100 ml of methanol, and then 5.90 g (53.6 mmol) of ammoniumdithiocarbamate was added thereto. The mixture was stirred at roomtemperature for 30 minutes. The solvent was distilled off under reducedpressure. To the residue, water was added to adjust the mixture topH2.0, and then the mixture was extracted twice with ethyl acetate. Theextract was dried over anhydrous sodium sulfate and-then concentrated.The crystal residue was washed with diethyl ether to obtain 8.80 g(yield: 72.9%) of the above-identified compound.

MP: 236° C. (solvent for recrystallization: ethyl acetate)

IR(KBr)cm⁻¹ : 3240, 1615, 1525, 1470

NMR(DMSO-d₆)δ: 6.77(1H, d, J=9Hz), 6.92(1H,s), 7.03(1H, dd, J=2 and9Hz), 7.08(1H, d, J=2Hz), 9.15(1H, m)

Elemental analysis value: as C₉ H₇ NO₂ S₂ Calculated value (%): C 47.98;H 3,13; N 6.21; S 28.47. Found value (%): C 48.07; H 3.02; N 6.22; S28.16.

Reference Example 6 Preparation of4-carboxy-5-(3,4-dihydroxyphenyl)-2-mercaptothiazole

(A) 60.1 g of piperonal as a starting material was treated in the samemanner as the method disclosed in Org. Syn., Coll. Vol. II, p.1-3,p.11-12 and p.519-520 to obtain 48.3 g (yield: 58%) of3-(3,4-methylenedioxyphenyl) pyruvic acid.

IR(KBr)cm⁻¹ : 1670, 1500, 1490, 1450, 1250, 1040

NMR(DMSO-d₆)δ: 6.03(2H, s), 6.38(1H, s), 6.87(1H, d, J=7.5Hz), 7.23(1H,d, J=7.5Hz), 7.46(1H, s), 9.00(2H, s)

(B) 10.4 g (0.05 mol) of the compound obtained in the above reaction

(A) was suspended in 100 ml of ethyl acetate, and 2.56 ml (0.05 mol) ofbromine was added thereto at -10° C. The mixture was stirred at the sametemperature for 10. minutes. To the reaction solution, 200 ml of ethanolwas added, and 9.92 g (0.09 mol) of ammonium dithiocarbanate was addedthereto at -10° C. The mixture was stirred at the same temperature for20 minutes and at room temperature for 2 hours. The reaction solutionwas cooled in an ice bath for 40 minutes. The insolubles were removed byfiltration and washed with 40 ml of ethyl acetate. The filtrate and thewashing solution were put together and concentrated under reducedpressure. To the residue, 350 ml of water was added, and the mixture washeated at 80° C. for 18 hours. Then, gummy insolubles were removed byfiltration under heating. The filtrate was adjusted to pH1.5 with 6Nhydrochloric acid under cooling with ice. The precipitates werecollected by filtration, washed with 30 ml of water and dried to obtain7.23 g of the above-identified compound as yellow powder.

Further, the above gummy insolubles were suspended in 20 ml of acetone.The insolubles were collected by filtration and dried to obtain 1.02 gof the secondary crystals. Total amount: 8.25 g (yield: 66%).

IR(KBr)cm⁻¹ : 1710, 1690, 1500, 1490, 1450, 1430, 1320, 1260, 1060, 1040

NMR(DMSO-d₆)δ: 6.10(2H, s), 6.97(2H, s), 7.12(1H, s), 12.0-15.0(2H, brs) (c) 6.79 g (0.024 mol) of the compound obtained in the above reaction

(B) was suspended in 180 ml of methylene chloride, and 13 ml ofethanethiol, and 16.0 g (0.12 mol) of anhydrous aluminum chloride wasadded thereto at 5° C. The mixture was stirred at the same temperaturefor 4 hours and at 10° C. for 24 hours. 100 ml of 6N hydrochloric acidwas dropwise added thereto under cooling with ice, and then the mixturewas stirred at the same temperature for 1.5 hours. The insolubles werecollected by filtration, washed twice with 50 ml of water and dried toobtain 5.35 g of a crude product. The crude product was recrystallizedfrom a solvent mixture of methanol/water to obtain 3.93 g (yield: 61%)of the above-identified compound as yellow needle crystals.

MP 245°-247° C. (decomposed)

IR(KBr)cm⁻¹ : 1710, 1700, 1610, 1520, 1480, 1350, 1300, 1250, 1210,1190, 1120, 1070, 1010

NMR(DMSO-d₆)δ: 5.00-7.50(2H, br s), 6.79(2H, s), 6.90(1H, s),8.00-10.0(2H, br s)

UV^(MeOH) _(max) mm(E^(1%) _(1cm)): 309.5(480), 340.5(481)

Reference Example 7 Preparation of4-(3,4-diacetoxyphenyl)-5-benzhydryloxy-carbonylmethyl-2-mercaptothiazole

(A) 70 g (0.7 mol) of succinic anhydride and 96.6 g (0.7 mol) ofveratrole were dissolved in 2,000 ml of methylene chloride, and 237 g(1.75 mol) of anhydrous aluminum chloride was added thereto at roomtemperature. The mixture was stirred at the same temperature for 6hours. The reaction solution was left to stand for 15 hours. Then, 1,600ml of 6N hydrochloric acid was dropwise added to the reaction solutionunder stirring and the mixture was further stirred for one hour. Theorganic layer was separated, and 300 ml of water was added thereto. Themixture was adjusted to pH7.5 with a saturated sodium bicarbonateaqueous solution. The aqueous layer was separated and adjusted to pH2.5with 6N hydrochloric acid. The aqueous layer was left to stand in arefrigerator for two days. Then, the precipitated crystals werecollected by filtration, washed with water and dried to obtain 106.8 g(yield: 64%) of 3-(3,4-dimethoxybenzoyl)propionic acid.

IR(KBr)cm⁻¹ : 3360, 1740, 1665, 1590, 1515, 1415, 1335, 1270, 1150,1020, 800, 770, 610

NMR(DMSO-d₆)δ: 2.56(2H, t, J=6.0Hz), 3.21(2H, t, J=6.0Hz), 3.93(3H, s),3.95(3H, s), 7.04(1H, d, J=8.7Hz), 7.45(1H, d, J=1.5Hz), 7.67(1H, dd,J=1.5 and 4.5Hz), 11.0-12.5(1H, br)

(B) To 106 g (0.445 mol) of the compound obtained in the above reaction,1,070 ml of 48% hydrobromic acid was added, and the mixture was refluxedat a boiling point for 5 hours. The solvent was distilled off underreduced pressure. To the residue, 1,000 ml of water was added and theresidue was dissolved under heating. Then, the solution was subjected totreatment by an activated carbon. The filtrate was kept under coolingovernight to obtain blackish brown crystals. This colored crystals weredissolved in 1,000 ml of water under heating, and the solution wassubjected to treatment by an activiated carbon twice. Then, the solutionwas kept under cooling overnight to obtain 37.2 g (yield: 39.8%) of3-(3,4-dihydroxybenzoyl)propionic acid as colorless plates.

IR(KBr)cm⁻¹ : 3460, 3370, 1740, 1660, 1590, 1405, 1380, 1245, 1165,1125, 885, 820, 610

NMR(DMSO-d₆)δ: 2.53(2H, t, J=6.2Hz), 3.12(2H, t, J=6.2Hz), 6.82(1H, d,J=8.7Hz), 7.30-7.50(2H, m), 9.00-10.50(2H, br), 11.30-12.80(1H, br)

(C) To 2.0 g (9.52 mmol) of the compound obtained in the above reaction

(B), 9.0 ml of acetic anhydride and 0.78 g (9.5 mmol) of sodium acetatewere added, and the mixture was refluxed under heating for 30 minutes.The solvent was distilled off under reduced pressure, and to theresidue, ethyl acetate was added. The mixture was washed with a 5%sodium bicarbonate aqueous solution and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by silica gel column chromatography(Wakogel C-300, 2% methanol/methylene chloride) to obtain 1.33 g (yield:50%) of 4-(3,4-diacetoxyphenyl)-2(3H)-furanone.

NMR(DMSO-d₆)δ: 2.30(6H, s), 3.58(2H, m), 6.24(1H, m), 7.30-7.60(3H, m)

(D) 300 mg (1.08 mmol) of the compound obtained in the above reaction(C) was dissolved in 8 ml of a mixed solvent of dioxane/water (3/1), and193 mg of N-bromosuccinimide was added thereto at room temperature. Themixture was stirred for 15 minutes. The reaction solution was pouredinto ethyl acetate, and the organic layer was dried over anhydrousmagnesium sulfate. Then, to the filtrate, 300 mg (1.54 mmol) ofdiphenyldiazomethane was added, and the mixture was stirred for onehour. The solvent was distilled off under reduced pressure, and theresidue was purified by silica gel column chromatography (Wakogel C-300,ethyl acetate/hexane=1/3) to obtain 350 mg (yield: 60%) of benzhydryl3-(3,4-diacetoxybenzoyl)-3-bromopropionate.

NMR(DMSO-d₆)δ: 2.33(6H, s), 3.20-3.80(2H, m), 6.00(1H, t, J=8.0Hz),6.80(1H, s), 7.10-7.60(13H, m)

(E) 700 mg (1.30 mmol) of the compound obtained in the above reactionwas dissolved in 7.0 ml of N,N-dimethylformamide, and 143 mg (1.30 mmol)of ammonium dithiocarbamate was added thereto under cooling with ice.The mixture was stirred for 15 minutes. The solvent was distilled offunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (Wakogel C-300, ethyl acetate/hexane=1/2) toobtain 470 mg (yield: 68%) of the above-identified compound.

IR(KBr)cm⁻¹ : 3400, 3240, 1750, 1735, 1500, 1470, 1370, 1260, 1200,1160, 1050

NMR(DMSO-d₆)δ: 6 2.30(6H, s), 3.00(2H, m), 4.40(1H, br t, J=7.0Hz),6.78(1H, s), 7.10-7.60(13H, m)

Reference Example 8 Preparation of5-(3,4-dihydroxyphenyl)-2-mercaptooxazole

(A) 10 g (53.6 mmol) of 2-chloro-3',4'-dihydroxyacetophenone wasdissolved in 50 ml of acetone, and 600 mg (4.0 mmol) of sodium iodideand 5.23 g (80.5 mmol) of sodium azide were added thereto. The mixturewas refluxed for 24 hours. The insolubles in the reaction solution wereremoved by filtration, and the filtrate was concentrated under reducedpressure. To the reaction solution, ethyl acetate was added, and themixture was washed sequentially with water and with a saturated sodiumchloride aqueous solution and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the oily residuewas dissolved in 100 ml of methanol and 13.6 ml of concentratedhydrochloric acid. 1.5 g of 10% palladium carbon catalyst was added tothe solution, and the mixture was stirred under heating at 40° C. undera hydrogen gas stream for 5 hours. The reaction solution was filtered,and the filtrate was concentrated under reduced pressure. To theconcentrated residue, actone was added, and the precipitated crystalswere collected by filtration to obtain 5.5 g (yield: 50.4%) of2-amino-3',4'-dihydroxyacetophenone hydrochloride.

NMR(DMSO-d₆ /D₂ O)δ: 4.40(2H, s), 6.90(1H, d, J=9.0Hz), 7.30-7.50(2H, m)

(B) 1.0 g (4.9 mmol) of the compound obtained in the above reaction (A)was suspended in 17 ml of an ethanol solution of 0.043N sodium ethoxide,and 2.1 ml (35 mmol) of carbon disulfide was added thereto. The mixturewas stirred at 60° C. for 20 hours. The reaction solution was pouredinto 50 ml of water, and the mixture was adjusted to pH1.5 with 6Nhydrochloric acid. The mixture was stirred for one hour and thenextracted with ethyl acetate. The organic layer was washed sequentiallywith water and with a saturated sodium chloride aqeous solution anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain 750 mg (yield: 73%) of the above-identifiedcompound.

MP: 215°-8° C.

IR(KBr)cm⁻¹ : 1640, 1600, 1520, 1500, 1300, 1180, 1120

NMR(DMSO-d₆ /D₂ O)δ: 6.70-6.95(2H, m ), 7.00(1H, s), 7.42(1H, s),

Elemental analysis value: as C₉ H₇ NO₃ S Calculated value: C 51.12; H3.12; N 6.43. Found value: C 51,67; H 3.37; N 6.69.

Reference Example 9 Preparation of2-mercapto-5,6-di(2-methoxyethoxymethoxy)benzimidazole

(A) 10 g (44 mmol) of 4,5-dimethoxy-1,2-dinitrobenzene was suspended in150 ml of 45% hydrobromic acid, and the suspension was refluxed at aboiling point for 6 hours. The reaction solution was allowed to cool toroom temperature, and 500 ml of water was added thereto. The mixture wasextracted three times with ethyl acetate. The organic layer was washedwith a 10% sodium bicarbonate aqueous solution and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The crystal residue was washed with methylene chloride to obtain 7 g(yield: 79%) of 4,5-dihydroxy1,2-dinitrobenzene.

NMR(DMSO-d₆)δ: 7.48(2H, s), 8.50(2H, br s)

(B) 28 g (0.14 mol) of the compound obtained in the above reaction (A)was suspended in 280 ml of methylene chloride, and 30 ml (0.42 mol) ofethyl diisopropylamine was added thereto at room temperature anddissolved. To the reaction solution, 30 ml (0.42 mol) of2-methoxyethoxymethyl chloride was dropwise added at 0° C., and themixture was stirred for 30 minutes. The reaction solution was pouredinto water. The organic layer was washed with a 1N sodium hydroxideaqueous solution, with a saturated sodium chloride aqueous solution anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain 39 g (yield: 74%) of4,5-di(2-methoxyethoxymethoxy)-1,2-dinitrobenzene.

IR(KBr)cm⁻¹ : 2900, 1525, 1362

NMR(DMSO-d₆)δ: 3.23(6H, s), 3.50(4H, m), 3.78(4H, m) 5.58(4H, s),8.01(2H, s) (C) 9.5 g (25 mmol) of the compound obtained in the abovereaction

(B) was dissolved in 180 ml of ethanol, and 1 g of a 10% palladiumcarbon catalyst was added thereto. Catalytic hydrogenation was conductedat 80° C. for 2 hours. 1 g of an additional 10% palladium carboncatalyst was added to the reaction solution, and the catalytichydrogenation was conducted under the same condition (this operation wasrepeated twice). The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue wassubjected to silica gel column chromatography (Wakogel C-300, ethylacetate/hexane=1/1). The eluted fraction containing the desired compoundwas concentrated to obtain 5.07 g (yield: 57%) of4,5-di(2-methoxyethoxymethoxy)-2-nitroaniline (the product was unstable,therefore promptly used for the subsequent reaction). (D) 3.5 g (10mmol) of the compound obtained in the above reaction (C) was dissolvedin 70 ml of ethanol, and 0.6 g of a 10% palladium carbon catalyst wasadded thereto. The catalytic hydrogenation was conducted at 80° C. forone hour. 0.6 g of an additional 10% palladium catalyst was furtheradded to the reaction solution, and the reduction reaction was conductedunder the same condition (this opration was repeated twice). Thecatalyst was removed by filtration, and then to the filtrate, 10 g (6.1mmol) of potassium O-ethyl dithiocarbonate and 3 ml of water were added.The mixture was refluxed at a boiling point for three hours. The solventwas distilled off under reduced pressure. The residue was dissolved inwater, and the solution was adjusted to pH3.0 with acetic acid andextracted three times with ethyl acetate. The organic layer was driedand concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography (Wakogel C-300, ethylacetate/hexane=3/1). The eluted fraction containing the desired compoundwas concentrated to obtain2-mercapto-5,6-di(2-methoxyethoxymethoxy)benz-imidazole (yield: 61%).

IR(KBr)cm⁻¹ : 3280, 1622, 1475, 1322

NMR(DMSO-d₆)δ: 3.25(6H, s), 3.32(2H, s), 3.48(4H, m), 3.75(4H, m),5.20(4H, s), 6.94(2H, s)

Reference Example 10 Preparation of2-mercapto-5,6-di(2-methoxyethoxymethoxy)-1-methylbenzimidazole

(A) 1.57 g (4.54 mmol) of 4,5-di(2-methoxyethoxymethoxy)-2-nitroanilineobtained in step

(C) of Reference Example 34 was dissolved in 16 ml ofN,N-dimethylformamide, and 2 g (8.63 mmol) of silver oxide and 10 ml(160 mmol) of methyl iodide were added thereto. The mixture was stirredat room temperature for one hour. The solvent was distilled off underreduced pressure, and the residue was subjected to silica gel columnchromatography (Wakogel C-300, ethyl acetate/hexane=1/1). The elutedfraction containing the desired compound was concentrated to obtain 0.85g of crude 4,5-di(2-methoxyethoxymethoxy)-N-methyl-2-nitroaniline.

(B) 0.85 g of the orude product obtained in the above reaction (A) wasdissolved in 16 ml of ethanol, and 0.4 g of a 10% palladium carboncatalyst was added thereto. The catalytic hydrogenation was conducted at80° C. for two hours. The catalyst was removed by filtration, and thento the filtrate, 1 g (6.25 mmol) of potassium O-ethyl dithiocarbonatewas added. The mixture was refluxed at a boiling point for two hours.The reaction solution was concentrated under reduced pressure, and theresidue was dissolved in water. The solution was adjusted to pH5.0 withacetic acid and then extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate and the solvent was distilled offunder reduced pressure. The residue was subjected to silica gel columnchromatography (Wakogel C-300, ethyl acetate/hexane=3/1) to obtain 67 mgof the above-identified compound.

NMR(CDCl₃)δ: 3.40(6H, s), 3.60(4H, m), 3.68(3H, s), 3.88(4H, m),5.27(2H, s), 5.30(2H, s), 7.02(1H, s), 7.08(1H, s)

Reference Example 11 Preparation of2-mercapto-5,6-di(2-methoxyethoxymethoxy)-benzoxazole

(A) 5.4 g (17 mmol) of 3,4-di(2-methoxyethoxymethoxy)-benzaldehyde wasdissolved in 216 ml of methylene chloride, and 4.4 g (20 mmol) of 80%m-chloroperbenzoic acid was added thereto. The mixture was refluxed at aboiling point for 20 hours. The reaction solution was washed with asodium bicarbonate aqueous solution and with a saturated sodium chlorideaqueous solution and then dried. The solvent was distilled off underreduced pressure to obtain 4.85 g (yield: 86%) ofO-formyl-3,4-di(2-methoxyethoxymethoxy)phenol. The product was used forthe subsequent reaction without purification.

NMR(CDCl₃ /DMSO-d₆)δ: 3.36(6H, s), 3.58(4H, m), 3.82(4H, m), 5.28(4H, brs), 6.73(1H, dd, J=2 and 9Hz), 7.02(1H, d, J=2Hz), 7.29(1H, d, J=9Hz)

(B) 4.85 g (14.7 mmol) of the compound obtained in the above reaction

(A) was dissolved in 4 ml of methanol, and 7.0 ml (17.6 mmol) of 10%sodium hydroxide was added thereto. The mixture was stirred at roomtemperature for 30 minutes. The reaction solution was poured into 1,000ml of water, and the mixture was washed with ethyl acetate. The aqueouslayer was adjusted to pH5.0 with 6N hydrochloric acid and extracted withethyl acetate. After drying over anhydrous sodium sulfate, the solventwas distilled off under reduced pressure, the residue was dissolved in 8ml of acetic acid, and 0.70 ml (11 mmol) of concentrated nitric acid wasadded thereto at 10° C. The mixture was stirred for 1 hour. The reactionsolution was poured into ethyl acetate and washed sequentially withwater and with a saturated sodium bicarbonate aqueous solution. Theorganic layer was dried and concentrated. The residue was subjected tosilica gel column chromatography (Wakogel C-300, ethylacetate/hexane=1/1). The eluted fraction containing the desired compoundwas concentrated to obtain 1.51 g (yield: 29.6%) of4,5-di(2-methoxyethoxymethoxy)-2-nitrophenol.

NMR(DMSO-d₆)δ: 3.25(6H, s), 3.50(4H, m), 3.76(4H, m), 5.23(4H, s),6.87(1H, s), 7.75(1H, s)

(C) 1.5 g (4.3 mmol) of the compound obtained in the above reaction (B)was dissolved in 30 ml of ethanol, and 0.5 g of a 10% palladium carboncatalyst was added thereto. The catalytic hydrogenation was conducted at70° C. for 1.5 hours. The catalyst was removed by filtration, and thento the filtrate, 0.36 9 (4.73 mmol) of carbon disulfide, 0.35 g (5.0mmol) of a 80% potassium hydroxide aqueous solution and 0.78 ml (43mmol) of water were added. The mixture was refluxed at a boiling pointfor 1.5 hours. The solvent was distilled off under reduced pressure, andthe residue was dissolved in water. The solution was adjusted to pH5.0with 6N hydrochloric acid and then extracted with ethyl acetate. Theorganic layer was dried and concentrated. The residue was subjected tosilica gel column chromatography (Wakogel C-300, ethylacetate/hexane=1/1) to obtain 857 mg (yield: 55.5%) of theabove-identified compound.

NMR(DMSO-d₆)δ: 3.22(6H, s), 3.46(4H, m), 3.75(4H, m), 5.23(4H, s),7.00(1H, s), 7.34(1H, s)

INDUSTRIAL APPLICABILITY

As aforementioned, the cephalosporin derivatives according to thepresent invention are useful as antibacterial agents and can be used forthe treatment of human infectious diseases caused by sensitive andresistant Gram-positive and Gram-nagative bacteria, particularlyGram-nagative bacteria including glucose non-fermentative Gram-nagativerods such as Pseudomonas aeruginosa, Pseudomomas cepacia, Pseudomonasmaltophilia and Acinetobacter calcoaceticus.

Further, the 1-carboxy-1-vinyl acetic acid derivatives are useful as theintermediates of said cephalosporin derivatives.

We claim:
 1. A compound having the formula: ##STR15## wherein X isCOO.sup.(-) or COOR, wherein R is a hydrogen atom or acarboxyl-protecting group and Q is a group having the formula: ##STR16##wherein each of Ra, R^(b) and R^(c) which may be the same or differentis a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group or a C₂₋₃ alkynyl group, ortwo or three of R^(a), R^(b) and R^(c) bond to each other and togetherwith the adjacent nitrogen atom, form a monocyclic ring, polycyclic ringor cross-linked polycyclic ring group selected from the group consistingof an azetidino group, a pyrrolidino group, a piperidino group a3-oxopiperidino group, a 4-oxopiperidino group, a1,2,3,6-tetrahydropiperidino group, a hexamethyleneimino group, amorpholino group, a thiomorpholino group, a 2-oxomorpholino group, apiperadino group, a homopiperadino group, a 3-oxopiperidino group, anisoindolino group, a 1,2,3,4-tetrahydroisoquinolino group, a2,3,4,5-tetrahydro-1H-2-benzazepino group, a1,2,4,5-tetraohydro-3H-3-benzazepino group, an imidazolino group, apyrimidino group, an oxozolino group, a pyridazino group, a thiazolinogroup, a pyridino group, quinolino group, an isoquinolino group,1H-imidazo[4,5-b]pyridino group, a thiazolo [4,5-b]pyridino group, anoxazo [ 4,5-b]pyridino group, a 1H-2-methylimidazo [4,5-b]pyridinogroup, a 3-methyl-3H-imidazo[4,5-b]pyridino group, a1-methyl-1H-imidazolo[4,5-c]pyridino group, a 4-(oxazol-2-yl)pyridinogroup, a 4-(4,5-dihydrooxazol-2-yl)pyridino group, a2,3-cyclopentenopyridino group, a 3,4-cyclopentenopyridino group, a3,4-cyclohexenopyridino group, a 1-azoniabicyclo [2,2,1]heptan-1-ylgroup, a 1-aoniabicyclo[3,3,1]nonan-1-yl group, a quinuclidino group anda 2-dehydroquinuclidino group, or a non-toxic salt or physiologicallyhydrolyzable non-toxic ester thereof.
 2. The compound according to claim1, wherein Q is a tri(C₁₋₆ alkyl)ammonio group, an N-C₂₋₆alkenyl-N,N-di(C₁₋₆ alkyl)ammonio group, N-C₂₋₃ alkynyl-N,N-di(C₁₋₆alkyl)ammonio group, an N-aralkyl-N,N-di(C₁₋₆ alkyl)ammonio group, agroup having the formula: ##STR17## wherein two or three of R^(a), R^(b)and R^(c) bond to each other and together with the adjacent nitrogenatom, form a monocyclic ring, polycyclic ring, or cross-linkedpolycyclic ring group selected from the group consisting of an azetidinogroup, a piperidino group, a 3-oxopiperidino group, a 4-oxopiperidinogroup, a 1,2,3,6-tetrahydropiperidino group, a hexamethyleneimino group,a morpholino group, a thiomorpholino group, a 2-oxomorpholinic group, apiperadino group, a homopiperadino group, a 3-oxopiperadino group, anisoindolino group, a 1,2,3,4-tetrahydroisoquinolino group, a2,3,4,5-tetrahydro-1H-2-benzazepino group, a1,2,4,5-tetrahydro-3H-3-benzazepino group, an imidazolino group, apyrimidino group, an oxazolino group, a pyridazino group, a thiazolinogroup, a pyridino group, a quinolino group, an isoquinolino group, a2,3-cyclopentenopyridino group, a 1-azoniabicyclo[3.3.1]heptane-1-ylgroup, a 1-azoniabicyclo[3.3.1]nonan-1-yl group, a quinuclidino groupand an 2-dehydroquinuclidino group wherein each of said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₃ alkynyl, aralkyl, monocyclic ring, polycyclic ring andcross-linked polycyclic ring groups may be substituted by one or moresubstituents which may be the same or different, selected from the groupconsisting of a hydroxyl group, a C₁₋₆ alkoxy group, a formyl group, analkanoyl group, a carbamoyloxy group, a di(C₁₋₆ alkyl)carboyloxy group,a carboxyl group, a C₁₋₆ alkoxycarbony group, a carbamoyl group, a cyanogroup, a sulfo group, an acetamido group, a sulfamoyl group, an aminogroup, a di(C₁₋₆ alkyl)amino group, a halogen atom and a phenyl, anoxazolyl, a thiazolyl, an oxadiazolyl and a tetrazolyl group which maybe substituted by one or more substituents which may be the same ordifferent, selected from the group consisting of a hydroxyl group, anacetoxy group and a carbamoyloxy group.
 3. The compound according toclaim 1, wherein Q is the group having the formula A and is a pyridino,a 2,3-cyclopentenopyridino, a quinuclindino or a 2-dehydroquinuclindinogroup which may be substituted by one or more substituents selected fromthe group consisting of a hydroxyl group, a carboxyl group, acarboxy-C₁₋₆ alkyl group, a carbamoyl group, a sulfo group, a sulfo-C₁₋₆alkyl group, an amino group, a formamido group and a phenyl group whichmay be substituted y one or more substituents selected from the groupconsisting of a hydroxyl group, an alkanoyl group and a carbamoyloxygroup.
 4. The compound according to claim 1, wherein Q is the grouphaving the formula A and is a trimethylammonio group, a triethylammoniogroup, a tripopylammonio group, anN-(2-hydroxyethyl)-N,N-dimethylammonio group, anN-(2-methoxyethyl)-N,N-dimethylammonio group, an N-(2-methoxyethyl)-N,N-dimethylammonio group, anN-(2-formyloxyethyl)-N,N-dimethylammonio group, anN[2-(3-oxobutyl)ethyl]-N,N-dimethylammonio group, anN-(2-carbomoyloxyethyl)-N,N-dimethylammonio group, anN[2-(N,N-dimethylcarbamoyloxy)ethyl]-N,N-dimethylammonio group,N-(2-carboxyethyl)-N,N-dimethylammonio group, anN-(2-carbamoylethyl)-N,N-dimethylammonio group, anN-(2-cyanoethyl)-N,N-dimethylammonio group, anN-(2-sulfoethyl)-N,N-dimethylammonio group, anN-(2-sulfamoylethyl)-N,N-dimethylammonio group, anN-(2-aminoethyl)-N,N-dimethylammonio group, anN-[2-(N,N-dimethylamino)ethyl]-N,N-dimethylammonio group, anN-phenethyl-N,N-dimethylammonio group, an N-allyl-N,N-dimethylammoniogroup, an N-propargyl-N,N-dimethylammonio group and anN-(2-fluoroethyl)-N,N-dimethylammonio group.
 5. The compound accordingto claim 1,wherein Q is a pyridino or a 2,3-cyclopentenopyridino groupwhich may be substituted by one or more substituents selected from thegroup consisting of a carboxyl group, a calboxy-C₁₋₆ alkyl group, acarbamoyl group, a sulfo-C₁₋₆ alkyl group, an amino group, a formamidogroup, a 3,4-dihydroxyphenyl group and a 3,4-diacetoxyphenyl group. 6.The compound according to claim 1, which is7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(1-pyridino)methyl-3-cephem-4-carboxylate(synisomer),7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido-3-(2,3-cyclopenteno-1-pyridino)methyl-3-cephem-4-carboxylate(syn-isomer),7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-carboxy-1-pyridino)methyl-3-cephem-4-carboxylate(syn isomer),7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3(3-carbamoyl-1-pyridino)methyl-3-cephem-4-carboxylate-syn-isomer),7β-[2-(2-aminothiazol-4yl-)-2-(1-carboxy-1-vinyloxyimino)acetamido[-3-[4-(2-sulfonatoethyl)-1-pyridino]methyl-3-cephem-4-carboxylicacid (syn-isomer),7β-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinylosyimino)acetamido]-3-(3-amino-1-pyridino)methyl-3-cephem-4-carboxylate(syn-isomer) or7β-[2(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamido]-3-(3-formylamino--pyridino)methyl-3-cephem-4-carboxylate(syn-isomer).
 7. The compound according to claim 1, wherein saidcarboxyl-protecting group is t-butyl, 2,2,2-trichloroethyl,acetoxylmethyl, propionyloxymethyl, pivaloyloxymethyl, 1-acetoxyethyl,1-propionyloxyethyl, 1-(ethoxycarbonyloxy)ethyl, phthalidyl, benzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-nitrobenzyl, benzhydryl,bis(4-methoxyphenyl)methyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,trimethylsilyl or p-butyldimethylsilyl.
 8. An antibacterial compositioncomprising an effective amount of a compound as claimed in claim 1, or anon-toxic salt of physiologically hydrolyzalbe non-toxic ester thereof,in admixture with a pharmaceutically acceptable carrier.